Modulators of LXR

ABSTRACT

Compounds of the invention, such as compounds of formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             where n, m, A, B, R 1 , R 2 , R 3 , R 4  and R 5  are defined herein, are useful as modulators of the activity of liver X receptors. Pharmaceutical compositions containing the compounds and methods of using the compounds are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.10/899,458, which is a continuation-in-part of the U.S. patentapplication Ser. No. 10/327,813, filed Dec. 20, 2002, which claims thebenefit of priority to U.S. Provisional Patent Application Ser. No.60/342,707, filed Dec. 21, 2001, the disclosures of which areincorporated herein in their entireties.

FIELD OF THE INVENTION

Compounds, compositions and methods for modulating the activity of liverX receptors (LXRs) are provided. In particular, pyridone derivatives areprovided for modulating the activity of LXRs.

BACKGROUND OF THE INVENTION

Nuclear Receptors

Nuclear receptors are a superfamily of regulatory proteins that arestructurally and functionally related and are receptors for, e.g.,steroids, retinoids, vitamin D and thyroid hormones (see, e.g., Evans(1988) Science 240:889-895). These proteins bind to cis-acting elementsin the promoters of their target genes and modulate gene expression inresponse to ligands for the receptors.

Nuclear receptors can be classified based on their DNA bindingproperties (see, e.g., Evans, supra and Glass (1994) Endocr. Rev.15:391-407). For example, one class of nuclear receptors includes theglucocorticoid, estrogen, androgen, progestin and mineralocorticoidreceptors which bind as homodimers to hormone response elements (HREs)organized as inverted repeats (see, e.g., Glass, supra). A second classof receptors, including those activated by retinoic acid, thyroidhormone, vitamin D₃, fatty acids/peroxisome proliferators (i.e.,peroxisome proliferator activated receptors or PPARs) and ecdysone, bindto HREs as heterodimers with a common partner, the retinoid X receptors(i.e., RXRs, also known as the 9-cis retinoic acid receptors; see, e.g.,Levin et al. (1992) Nature 355:359-361 and Heyman et al. (1992) Cell68:397-406).

RXRs are unique among the nuclear receptors in that they bind DNA as ahomodimer and are required as a heterodimeric partner for a number ofadditional nuclear receptors to bind DNA (see, e.g., Mangelsdorf et al.(1995) Cell 83:841-850). The latter receptors, termed the class IInuclear receptor subfamily, include many which are established orimplicated as important regulators of gene expression. There are threeRXR genes (see, e.g., Mangelsdorf et al. (1992) Genes Dev. 6:329-344),coding for RXRα, -β, and -γ, all of which are able to heterodimerizewith any of the class II receptors, although there appear to bepreferences for distinct RXR subtypes by partner receptors in vivo (see,e.g., Chiba et al. (1997) Mol. Cell. Biol. 17:3013-3020). In the adultliver, RXRα is the most abundant of the three RXRs (see, e.g.,Mangelsdorf et al. (1992) Genes Dev. 6:329-344), suggesting that itmight have a prominent role in hepatic functions that involve regulationby class II nuclear receptors. See also, Wan et al. (2000) Mol. Cell.Biol. 20:4436-4444.

Orphan Nuclear Receptors

Included in the nuclear receptor superfamily of regulatory proteins arenuclear receptors for whom the ligand is known and those which lackknown ligands. Nuclear receptors falling in the latter category arereferred to as orphan nuclear receptors. The search for activators fororphan receptors has led to the discovery of previously unknownsignaling pathways (see, e.g., Levin et al., (1992), supra and Heyman etal., (1992), supra). For example, it has been reported that bile acids,which are involved in physiological processes such as cholesterolcatabolism, are ligands for farnesoid X receptor (FXR).

Since it is known that products of intermediary metabolism act astranscriptional regulators in bacteria and yeast, such molecules mayserve similar functions in higher organisms (see, e.g., Tomkins (1975)Science 189:760-763 and O'Malley (1989) Endocrinology 125:1119-1120).For example, one biosynthetic pathway in higher eukaryotes is themevalonate pathway, which leads to the synthesis of cholesterol, bileacids, porphyrin, dolichol, ubiquinone, carotenoids, retinoids, vitaminD, steroid hormones and farnesylated proteins.

LXRα and LXRβ

LXRα is found predominantly in the liver, with lower levels found inkidney, intestine, spleen and adrenal tissue (see, e.g., Willy, et al.(1995) Gene Dev. 9(9):1033-1045). LXRβ is ubiquitous in mammals and wasfound in nearly all tissues examined. LXRs are activated by certainnaturally occurring, oxidized derivatives of cholesterol (see, e.g.,Lehmann, et al. (1997) J. Biol. Chem. 272(6):3137-3140). LXRα isactivated by oxycholesterol and promotes cholesterol metabolism (Peet etal. (1998) Cell 93:693-704). Thus, LXRs appear to play a role in, e.g.,cholesterol metabolism (see, e.g., Janowski, et al. (1996) Nature383:728-731).

Nuclear Receptors and Disease

Nuclear receptor activity has been implicated in a variety of diseasesand disorders, including, but not limited to, hypercholesterolemia (see,e.g., International Patent Application Publication No. WO 00/57915),osteoporosis and vitamin deficiency (see, e.g., U.S. Pat. No.6,316,5103), hyperlipoproteinemia (see, e.g., International PatentApplication Publication No. WO 01/60818), hypertriglyceridemia,lipodystrophy, hyperglycemia and diabetes mellitus (see, e.g.,International Patent Application Publication No. WO 01/82917),atherosclerosis and gallstones (see, e.g., International PatentApplication Publication No. WO 00/37077), disorders of the skin andmucous membranes (see, e.g., U.S. Pat. Nos. 6,184,215 and 6,187,814, andInternational Patent Application Publication No. WO 98/32444), acne(see, e.g., International Patent Application Publication No. WO00/49992), and cancer, Parkinson's disease and Alzheimer's disease (see,e.g., International Patent Application Publication No. WO 00/17334).Activity of nuclear receptors, including LXRs, FXR and PPAR, and orphannuclear receptors, has been implicated in physiological processesincluding, but not limited to, bile acid biosynthesis, cholesterolmetabolism or catabolism, and modulation of cholesterol 7α-hydroxylasegene (CYP7A1) transcription (see, e.g., Chiang et al. (2000) J. Biol.Chem. 275:10918-10924), HDL metabolism (see, e.g., Urizar et al. (2000)J. Biol. Chem. 275:39313-39317 and International Patent ApplicationPublication No. WO 01/03705), and increased cholesterol efflux andincreased expression of ATP binding cassette transporter protein (ABC1)(see, e.g., International Patent Application Publication No. WO00/78972).

Thus, there is a need for compounds, compositions and methods ofmodulating the activity of nuclear receptors, including LXRs, FXR, PPARand orphan nuclear receptors. Such compounds are useful in thetreatment, prevention, or amelioration of one or more symptoms ofdiseases or disorders in which nuclear receptor activity is implicated.

SUMMARY OF THE INVENTION

Compounds for use in compositions and methods for modulating theactivity of nuclear receptors are provided. In particular, compounds foruse in compositions and methods for modulating liver X receptors (LXRαand LXRβ), FXR, PPAR and/or orphan nuclear receptors are provided. Incertain embodiments, the compounds are N-substituted pyridone compounds.In one embodiment, the compounds provided herein are agonists of LXR. Inanother embodiment, the compounds provided herein are antagonists ofLXR. Agonists that exhibit low efficacy are, in certain embodiments,antagonists.

Accordingly, one aspect of this invention is directed to compounds offormula (I):

wherein:

n is 1 to 4;

m is 1 to 4;

is aryl or heteroaryl;

is aryl, heterocyclyl or heteroaryl;

R¹ is hydrogen, aralkyl or heteroarylalkyl;

R² is hydrogen, cyano, —R⁷—N(R⁸)₂, —R⁷—N(R⁸)S(O)₂R¹⁰ or—R⁷—N(R⁸)C(NR⁸)N(R⁸)₂;

R³ is hydrogen, alkyl, alkenyl, aralkyl, aralkenyl, haloalkyl,haloalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl;

each R⁴ is independently hydrogen, halo, alkyl or haloalkyl;

each R⁵ is independently selected from the group consisting of hydrogen,halo, nitro, alkyl, alkenyl, aryl, aralkyl, aralkenyl, haloalkyl,haloalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁷—CN, —R⁷—N(R⁸)₂,—R⁷—OR⁸, —R⁷—O—R⁹—C(O)OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂,—R⁷—C(O)N(R⁸)OR⁸, —R⁷—C(O)N(R⁸)N(R⁸)₂, —R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸,—R⁷—C(S)N(R⁸)₂, —R⁷—N(R⁸)C(O)R⁸, —R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—S(O)_(t)R⁸(where t is 0 to 2) and —R⁷—S(O)₂N(R⁸)₂;

R⁶ is —OR⁷—, —N(R⁸)—, a direct bond, a straight or branched alkylenechain, a straight or branched alkenylene chain or a straight or branchedalkynylene chain;

each R⁷ is independently selected from a direct bond, a straight orbranched alkylene chain or a straight or branched alkenylene chain;

each R⁸ is independently selected from hydrogen, alkyl, alkenyl,haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl;

each R⁹ is independently selected from a straight or branched alkylenechain or a straight or branched alkenylene chain;

each R¹⁰ is independently selected from alkyl, aryl, aralkyl orcycloalkylalkyl; and

R¹¹ is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heterarylalkyl;

as an isomer, a mixture of stereoisomers, a racemic mixture thereof ofstereoisomers, or as a tautomer;

or as a pharmaceutically acceptable salt, prodrug, solvate or polymorphthereof.

Another aspect of this invention is directed to methods of treating,preventing, or ameliorating the symptoms of a disease or disorder thatis modulated or otherwise affected by nuclear receptor activity or inwhich nuclear receptor activity is implicated, comprising administeringto a subject in need thereof an effective amount of a compound offormula (I) as set forth above, or a pharmaceutically acceptablederivative thereof.

Another aspect of this invention is directed to methods of reducingcholesterol levels in a subject in need thereof, comprisingadministering an effective amount of a compound of formula (I) as setforth above, or a pharmaceutically acceptable derivative thereof.

Another aspect of this invention is directed to methods of treating,preventing, or ameliorating one or more symptoms of a disease ordisorder which is affected by cholesterol, triglyceride, or bile acidlevels, comprising administering to a subject in need thereof aneffective amount of a compound of formula (I) as set forth above, or apharmaceutically acceptable derivative thereof.

Another aspect of this invention is directed to methods of modulatingnuclear receptor activity, comprising contacting the nuclear receptorwith a compound of formula (I) as set forth above, or a pharmaceuticallyacceptable derivative thereof.

Another aspect of this invention is directed to methods of modulatingcholesterol metabolism, comprising administering an effective amount ofa compound of formula (I) as set forth above, or a pharmaceuticallyacceptable derivative thereof.

Another aspect of this invention is directed to methods of treating,preventing or ameliorating one or more symptoms of hypocholesterolemiain a subject in need thereof, comprising administering an effectiveamount of a compound of formula (I) as set forth above, or apharmaceutically acceptable derivative thereof.

Another aspect of this invention is directed to methods of increasingcholesterol efflux from cells of a subject, comprising administering aneffective amount of a compound of formula (I) as set forth above, or apharmaceutically acceptable derivative thereof.

Another aspect of this invention is directed to methods of increasingthe expression of ATP-Binding Cassette (ABC1) in the cells of a subject,comprising administering an effective amount of a compound of formula(I) as set forth above, or a pharmaceutically acceptable derivativethereof.

Another aspect of this invention is directed to in vitro methods foraltering nuclear receptor activity, comprising contacting the nuclearreceptor with a compound of formula (I) as set forth above, or apharmaceutically acceptable derivative thereof.

Another aspect of this invention is directed to methods of reducingcholesterol levels in a subject in need thereof, comprisingadministering an effective amount of a compound of formula (I) as setforth above, or a pharmaceutically acceptable derivative thereof.

Another aspect of this invention is directed to pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and acompound of formula (I) as set forth above.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. For example, “acompound” refers to one or more of such compounds, while “the enzyme”includes a particular enzyme as well as other family members andequivalents thereof as known to those skilled in the art.

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight, and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. Unlessstated otherwise specifically in the specification, the alkyl radicalmay be optionally substituted by one or more substituents selected fromthe group consisting of halo, cyano, nitro, —OR⁸, —N(R⁸)₂, —C(O)R⁸,—C(O)OR⁸, —C(O)N(R⁸)₂, —N(R⁸)C(O)OR¹⁰, —N(R⁸)C(O)R⁸, —N[S(O)_(t)R⁸]₂(where t is 0 to 2), —N(R⁸)S(O)_(t)R⁸ (where t is 0 to 2), —S(O)_(p)OR⁸(where p is 1 to 2), —S(O)_(t)R⁸ (where t is 0 to 2), and—S(O)_(p)N(R⁸)₂ (where p is 1 to 2) where each R⁸ and R¹⁰ is as definedabove in the Summary of the Invention. Unless stated otherwisespecifically in the specification, it is understood that for radicals,as defined below, that contain a substituted alkyl group that thesubstitution can occur on any carbon of the alkyl group.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from two to eight carbon atoms, and which isattached to the rest of the molecule by a single bond or a double bond,e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl,and the like. Unless stated otherwise specifically in the specification,the alkenyl radical may be optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,—OR⁸, —N(R⁸)₂, —C(O)R⁸, —C(O)OR⁸, —C(O)N(R⁸)₂, —N(R⁸)C(O)OR¹⁰,—N(R⁸)C(O)R⁸, —N[S(O)_(t)R⁸]₂ (where t is 0 to 2), —N(R⁸)S(O)_(t)R⁸(where t is 0 to 2), —S(O)_(p)OR⁸ (where p is 1 to 2), —S(O)_(t)R⁸(where t is 0 to 2), and —S(O)_(p)N(R⁸)₂ (where p is 1 to 2) where eachR⁸ and R¹⁰ is as defined above in the Summary of the Invention. Unlessstated otherwise specifically in the specification, it is understoodthat for radicals, as defined below, that contain a substituted alkenylgroup that the substitution can occur on any carbon of the alkenylgroup.

“Aryl” refers to refers to aromatic monocyclic or multicyclic ringsystem containing from 6 to 19 carbon atoms, where the ring system maybe partially or fully saturated. Aryl groups include, but are notlimited to groups such as fluorenyl, phenyl and naphthyl. Unless statedotherwise specifically in the specification, the term “aryl” or theprefix “ar-” (such as in “aralkyl”) is meant to include aryl radicalsoptionally substituted by one or more substituents selected from thegroup consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano,nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —R⁷—OR⁸, —R⁷—N(R⁸)₂,—R⁷—C(O)R⁸, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—N(R⁸)C(O)OR¹⁰,—R⁷—N(R⁸)C(O)R⁸, —R⁷—N[S(O)_(t)R⁸]₂ (where t is 0 to 2),—R⁷—N(R⁸)S(O)_(t)R⁸ (where t is 0 to 2), —R⁷—S(O)_(p)OR⁸ (where p is 1to 2), —R⁷—S(O)_(t)R⁸ (where t is 0 to 2), and —R⁷—S(O)_(p)N(R⁸)₂ (wherep is 1 to 2) where each R⁸, R⁷ and R¹⁰ is as defined above in theSummary of the Invention.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isan alkyl radical as defined above and R_(b) is one or more aryl radicalsas defined above, e.g., benzyl, diphenylmethyl and the like. The arylradical(s) and the alkyl radical may be optionally substituted asdescribed above.

“Alkylene” and “alkylene chain” refer to a straight or branched divalenthydrocarbon chain, linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, preferably having from one toeight carbons, e.g., methylene, ethylene, propylene, n-butylene, and thelike. The alkylene chain may be attached to the rest of the molecule andto the radical group through one carbon within the chain or through anytwo carbons within the chain. The alkylene chain may be optionallysubstituted by one or more substituents selected from the groupconsisting of halo, cyano, nitro, aryl, cycloalkyl, heteroaryl,heterocyclyl, —OR⁸, —N(R⁸)₂, —C(O)R⁸, —C(O)OR⁸, —C(O)N(R⁸)₂,—N(R⁸)C(O)OR¹⁰, —N(R⁸)C(O)R⁸, —N[S(O)_(t)R⁸]₂ (where t is 0 to 2),—N(R⁸)S(O)_(t)R⁸ (where t is 0 to 2), —S(O)_(p)OR⁸ (where p is 1 to 2),—S(O)_(t)R⁸ (where t is 0 to 2), and —S(O)_(p)N(R⁸)₂ (where p is 1 to 2)where each R⁸ and R¹⁰ is as defined above in the Summary of theInvention. The alkylene chain may be attached to the rest of themolecule through any two carbons within the chain.

“Alkenylene” and “alkenylene chain” refer to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, e.g.,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a single bond andto the radical group through a double bond or a single bond. The pointsof attachment of the alkenylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain. The alkenylene chain may be optionally substituted by one ormore substituents selected from the group consisting of halo, cyano,nitro, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR⁸, —N(R⁸)₂,—C(O)R⁸, —C(O)OR⁸, —C(O)N(R⁸)₂, —N(R⁸)C(O)OR¹⁰, —N(R⁸)C(O)R⁸,—N[S(O)_(t)R⁸]₂ (where t is 0 to 2), —N(R⁸)S(O)_(t)R⁸ (where t is 0 to2), —S(O)_(p)OR⁸ (where p is 1 to 2), —S(O)_(t)R⁸ (where t is 0 to 2),and —S(O)_(p)N(R⁸)₂ (where p is 1 to 2) where each R⁸ and R¹⁰ is asdefined above in the Summary of the Invention.

“Alkynylene” and “alkynylene chain” refer to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onetriple bond and having from two to twelve carbon atoms, e.g.,ethynylene, propynylene, n-butenylene, and the like. The alkynylenechain is attached to the rest of the molecule through a single bond andto the radical group through a triple bond or a single bond. The pointsof attachment of the alkynylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain. The alkynylene chain may be optionally substituted by one ormore substituents selected from the group consisting of halo, cyano,nitro, aryl, cycloalkyl, heteroaryl, heterocyclyl, —OR⁸, —N(R⁸)₂,—C(O)R⁸, —C(O)OR⁸, —C(O)N(R⁸)₂, —N(R⁸)C(O)OR¹⁰, —N(R⁸)C(O)R⁸,—N[S(O)_(t)R⁸]₂ (where t is 0 to 2), —N(R⁸)S(O)_(t)R⁸ (where t is 0 to2), —S(O)_(p)OR⁸ (where p is 1 to 2), —S(O)_(t)R⁸ (where t is 0 to 2),and —S(O)_(p)N(R⁸)₂ (where p is 1 to 2) where each R⁸ and R¹⁰ is asdefined above in the Summary of the Invention.

“Cycloalkyl” refers to a stable monovalent monocyclic or bicyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having from three to ten carbon atoms, and which is saturated andattached to the rest of the molecule by a single bond, e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and thelike. Unless otherwise stated specifically in the specification, theterm “cycloalkyl” is meant to include cycloalkyl radicals which areoptionally substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkenyl, halo, haloalkyl,haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁷—OR⁸,—R⁷—N(R⁸)₂, —R⁷—C(O)R⁸, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—N(R⁸)C(O)OR¹⁰,—R⁷—N(R⁸)C(O)R⁸, —R⁷—N[S(O)_(t)R⁸]₂ (where t is 0 to 2),—R⁷—N(R⁸)S(O)_(t)R⁸ (where t is 0 to 2), —R⁷—S(O)_(p)OR⁸ (where p is 1to 2), and —R⁷—S(O)_(t)R⁸ (where t is 0 to 2), —R⁷—S(O)_(p)N(R⁸)₂ (wherep is 1 to 2) where each R⁸, R⁷ and R¹⁰ is as defined above in theSummary of the Invention.

“Cycloalkylalkyl” refers to a radical of the formula —R_(a)R_(d) whereR_(a) is an alkyl radical as defined above and R_(d) is a cycloalkylradical as defined above. The alkyl radical and the cycloalkyl radicalmay be optionally substituted as defined above.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,2-bromoethynyl, 3-bromoprop-1-enyl, and the like.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur. Forpurposes of this invention, the heterocyclyl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heterocyclyl radical may be optionally oxidized; thenitrogen atom may be optionally quaternized; and the heterocyclylradical may be partially or fully saturated. Examples of suchheterocyclyl radicals include, but are not limited to, dioxolanyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocyclyl” is meant to include heterocyclylradicals as defined above which are optionally substituted by one ormore substituents selected from the group consisting of alkyl, alkenyl,halo, haloalkyl, haloalkenyl, nitro, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —R⁷—OR⁸, —R⁷—N(R⁸)₂, —R⁷—CN, —R⁷—C(O)R⁸, —R⁷—C(O)OR⁸,—R⁷—C(O)N(R⁸)₂, —R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—N(R⁸)C(O)R⁸, —R⁷—N[S(O)_(t)R⁸]₂(where t is 0 to 2), —R⁷—N(R⁸)S(O)_(t)R⁸ (where t is 0 to 2),—R⁷—S(O)_(p)OR⁸ (where p is 1 to 2), —R⁷—S(O)_(t)R⁸ (where t is 0 to 2),and —R⁷—S(O)_(p)N(R⁸)₂ (where p is 1 to 2) where each R⁸, R⁷ and R¹⁰ isas defined above in the Summary of the Invention. For purposes of thisinvention, the term “N-heterocyclyl” refers to heterocyclyl radicals asdefined above containing at least one nitrogen atom in ring.

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)R_(e) whereR_(a) is an alkyl radical as defined above and R_(e) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. The heterocyclyl radical and thealkyl radical may be optionally substituted as defined above.

“Heteroaryl” refers to a 3- to 18-membered aromatic ring radical whichconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur. For purposes ofthis invention, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl,benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl,benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl,indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl,naphthyridinyl, oxadiazolyl, 2-oxazepinyl, oxazolyl, oxiranyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, phthalimidylpteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl,quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl,tetrazolyl, triazinyl, and thiophenyl. Unless stated otherwisespecifically in the specification, the term “heteroaryl” is meant toinclude heteroaryl radicals as defined above which are optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, nitro, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R⁷—OR⁸, —R⁷—N(R⁸)₂, —R⁷—CN, —R⁷—C(O)R⁸,—R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—N(R⁸)C(O)R⁸,—R⁷—N[S(O)_(t)R⁸]₂ (where t is 0 to 2), —R⁷—N(R⁸)S(O)_(t)R⁸ (where t is0 to 2), —R⁷—S(O)_(p)OR⁸ (where p is 1 to 2), —R⁷—S(O)_(t)R⁸ (where t is0 to 2), and —R⁷—S(O)_(p)N(R⁸)₂ (where p is 1 to 2) where each R⁸, R⁷and R¹⁰ is as defined above in the Summary of the Invention. Forpurposes of this invention, the term “N-heteroaryl” refers to heteroarylradicals as defined above containing at least one nitrogen atom in ring.

“Heteroarylalkyl” refers to a radical of the formula —R_(a)R_(f) whereR_(a) is an alkyl radical as defined above and R_(f) is a heteroarylradical as defined above, and if the heteroaryl is a nitrogen-containingheteroaryl, the heteroaryl may be attached to the alkyl radical at thenitrogen atom. The heteroaryl radical and the alkyl radical may beoptionally substituted as defined above.

As used herein, compounds which are “commercially available” may beobtained from standard commercial sources including Acros Organics(Pittsburgh Pa.), Aldrich Chemical (Milwaukee Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), AvocadoResearch (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester Pa.), Crescent ChemicalCo. (Hauppauge N.Y.), Eastman Organic Chemicals, Eastman Kodak Company(Rochester N.Y.), Fisher Scientific Co. (Pittsburgh Pa.), FisonsChemicals (Leicestershire UK), Frontier Scientific (Logan Utah), ICNBiomedicals, Inc. (Costa Mesa Calif.), Key Organics (Cornwall U.K.),Lancaster Synthesis (Windham N.H.), Maybridge Chemical Co. Ltd.(Cornwall U.K.), Parish Chemical Co. (Orem Utah), Pfaltz & Bauer, Inc.(Waterbury Conn.), Polyorganix (Houston Tex.), Pierce Chemical Co.(Rockford Ill.), Riedel de Haen AG (Hannover, Germany), Spectrum QualityProduct, Inc. (New Brunswick, N.J.), TCI America (Portland Oreg.), TransWorld Chemicals, Inc. (Rockville Md.), and Wako Chemicals USA, Inc.(Richmond Va.).

As used herein, “suitable conditions” for carrying out a synthetic stepare explicitly provided herein or may be discerned by reference topublications directed to methods used in synthetic organic chemistry.The reference books and treatise set forth above that detail thesynthesis of reactants useful in the preparation of compounds of thepresent invention, will also provide suitable conditions for carryingout a synthetic step according to the present invention.

As used herein, “methods known to one of ordinary skill in the art” maybe identified though various reference books and databases. Suitablereference books and treatise that detail the synthesis of reactantsuseful in the preparation of compounds of the present invention, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandier et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Specificand analogous reactants may also be identified through the indices ofknown chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C. may be contacted for more details).Chemicals that are known but not commercially available in catalogs maybe prepared by custom chemical synthesis houses, where many of thestandard chemical supply houses (e.g., those listed above) providecustom synthesis services.

“Prodrugs” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers which release the active compound of the invention in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention and the like.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and domestic animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals as defined herein and arylradicals having no substitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

“Pharmaceutically acceptable derivative” refers to pharmaceuticallyacceptable salts as defined herein and also includes esters, prodrugs,solvates and polymorphs of the compounds of the invention.

“Therapeutically effective amount” refers to that amount of a compoundof formula (I) which, when administered to a mammal, preferably a human,is sufficient to effect treatment, as defined below, for a disease-stateassociated the nuclear receptor activity. The amount of a compound offormula (I) which constitutes a “therapeutically effective amount” willvary depending on the compound, the condition and its severity, and theage of the mammal to be treated, but can be determined routinely by oneof ordinary skill in the art having regard to his own knowledge and tothis disclosure.

“Modulating” or “modulate” refers to the treating, prevention,suppression, enhancement or induction of a function or condition. Forexample, the compounds of the present invention can modulatehyperlipidemia by lowering cholesterol in a human, thereby suppressinghyperlipidemia.

“Treating” or “treatment” as used herein covers the treatment of adisease or condition associated with the nuclear receptor activity asdisclosed herein, in a mammal, preferably a human, and includes:

(i) preventing a disease or condition associated with the nuclearreceptor activity from occurring in a mammal, in particular, when suchmammal is predisposed to the disease or condition but has not yet beendiagnosed as having it;

(ii) inhibiting a disease or condition associated with the nuclearreceptor activity, i.e., arresting its development; or

(iii) relieving a disease or condition associated with the nuclearreceptor activity, i.e., causing regression of the condition.

The compounds of formula (I), or their pharmaceutically acceptable saltsmay contain one or more asymmetric centers and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as, their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as reverse phase HPLC. Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included.

The chemical naming protocol and structure diagrams used herein employand rely on the chemical naming features as utilized by the ChemDrawprogram (available from Cambridgesoft Corp., Cambridge, Mass.). Inparticular, the compound names were derived from the structures usingthe Autonom program as utilized by Chemdraw Ultra or ISIS base (MDLCorp.).

For example, a compound of formula (V) wherein n and m are each 1, Y issulfur, R¹ is 2,4-difluorobenzyl, R² is cyano, R³ is trifluoromethyl, R⁴is hydrogen,

is pyridin-3-yl, R⁵ is piperazin-1-yl and R⁶ is a direct bond, i.e., acompound of the following formula:

is named herein as1-(2,4-Difluoro-benzyl)-2-oxo-6-[4-(6-piperazin-1-yl-pyridin-3-yl)-thiophen-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile.

The term “atherosclerosis” refers to process whereby atheroscleroticplaques form within the inner lining of the artery wall leading toatherosclerotic cardiovascular diseases. Atherosclerotic cardiovasculardiseases can be recognized and understood by physicians practicing inthe relevant fields of medicine, and include without limitation,restenosis, coronary heart disease (also known as coronary artery heartdisease or ischemic heart disease), cerebrovascular disease includingischemic stroke, multi-infarct dementia, and peripheral vessel disease,including intermittent claudication, and erectile dysfunction.

The term “dyslipidemia” refers to abnormal levels of lipoproteins inblood plasma including both depressed and/or elevated levels oflipoproteins (e.g., elevated levels of Low Density Lipoprotein, (LDL),Very Low Density Lipoprotein (VLDL) and depressed levels of High DensityLipoprotein (HDL) (less than 40 mg/dL)).

As used herein, “EC₅₀” refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

The term “hyperlipidemia” refers to the presence of an abnormallyelevated level of lipids in the blood. Hyperlipidemia can appear in atleast three forms: (1) hypercholesterolemia, i.e., an elevated LDLcholesterol level (120 mg/dL and above); (2) hypertriglyceridemia, i.e.,an elevated triglyceride level; (150 mg/dL and above) and (3) combinedhyperlipidemia, i.e., a combination of hypercholesterolemia andhypertriglyceridemia.

As used herein, “IC₅₀” refers to an amount, concentration or dosage of aparticular test compound that achieves a 50% inhibition of a maximalresponse, such as modulation of nuclear receptor, including the LXRα orLXRβ activity, in an assay that measures such response.

As used herein, “LXR α” refers to all mammalian forms of such receptorincluding, for example, alternative splice isoforms and naturallyoccurring isoforms. Representative LXR α species include, withoutlimitation the rat (Genbank Accession NM_(—)031627) (SEQ ID NOS: 1-2),mouse (Genbank Accession BC012646) (SEQ ID NOS: 3-4), and human (GenBankAccession No. U22662) (SEQ ID NOS: 5-6) forms of the receptor.

As used herein, “LXR β” refers to all mammalian forms of such receptorincluding, for example, alternative splice isoforms and naturallyoccurring isoforms. Representative LXR β species include, withoutlimitation the rat (GenBank Accession NM 031626) (SEQ ID NOS: 7-8),mouse (Genbank Accession NM_(—)009473) (SEQ ID NOS: 9-10), and human(GenBank Accession No. U07132) (SEQ ID NOS: 11-12) forms of thereceptor.

As used herein “LXR” or “LXRs” refers to both LXRα and LXRβ.

The terms “obese” and “obesity” refers to a Body Mass Index (BMI)greater than 27.8 kg/m² for men and 27.3 kg m² for women (BMI equalsweight (kg)/height (m²).

Utility of the Compounds of the Invention

The compounds of the invention exhibit valuable pharmacologicalproperties in mammals, and are particularly useful as selective LXRagonists, antagonists, inverse agonists, partial agonists andantagonists, for the treatment, or prevention of diseases associatedwith, or symptoms arising from the complications of, altered cholesteroltransport, cholesterol reverse transport, fatty acid metabolism,cholesterol absorption, cholesterol re-absorption, cholesterolsecretion, cholesterol excretion, or cholesterol metabolism.

These diseases include, for example, hyperlipidemia, dyslipidemia,hypercholesterolemia, atherosclerosis, atherosclerotic cardiovasculardiseases, hyperlipoproteinemia, (see, e.g., Patent ApplicationPublication Nos. WO 00/57915 and WO 00/37077), hyperglycemia, insulinresistance, diabetes, lipodystrophy, obesity, syndrome X (US PatentApplication No. 20030073614, International Patent ApplicationPublication No. WO 01/82917), excess lipid deposition in peripheraltissues such as skin (xanthomas) (see, e.g., U.S. Pat. Nos. 6,184,215and 6,187,814), stroke, peripheral occlusive disease, memory loss (BrainResearch (1997), Vol. 752, pp. 189-196), optic nerve and retinalpathologies (i.e., macular degeneration, retinitis pigmentosa), repairof traumatic damage to the central or peripheral nervous system (Trendsin Neurosciences (1994), Vol. 17, pp. 525-530), prevention of thedegenerative process due to aging (American Journal of Pathology (1997),Vol. 151, pp. 1371-1377), Parkinson's disease or Alzheimer's disease(see, e.g., International Patent Application Publication No. WO00/17334; Trends in Neurosciences (1994), Vol. 17, pp. 525-530),prevention of degenerative neuropathies occurring in diseases such asdiabetic neuropathies (see, e.g., International Patent ApplicationPublication No. WO 01/82917), multiple sclerosis (Annals of ClinicalBiochem. (1996), Vol. 33, No. 2, pp. 148-150), and autoimmune diseases(J. Lipid Res. (1998), Vol. 39, pp. 1740-1743).

Also provided, are methods of increasing the expression of ATP-BindingCassette (ABCA1), (see, e.g., International Patent ApplicationPublication No. WO 00/78972) thereby increasing reverse cholesteroltransport in mammalian cells using the claimed compounds andcompositions.

Accordingly in another aspect, the invention also includes methods toremove cholesterol from tissue deposits such as atherosclerotic plaquesor xanthomas in a patient with atherosclerosis or atheroscleroticcardiovascular disease manifest by clinical signs of such disease,wherein the methods comprise administering to the patient atherapeutically effective amount of a compound or composition of thepresent invention.

Additionally, the instant invention also provides a method forpreventing or reducing the risk of a first or subsequent occurrence ofan atherosclerotic cardiovascular disease event including ischemic heartdisease, ischemic stroke, multi-infarct dementia, and intermittentclaudication comprising the administration of a prophylacticallyeffective amount of a compound or composition of the present inventionto a patient at risk for such an event. The patient may already haveatherosclerotic cardiovascular disease at the time of administration, ormay be at risk for developing it. Risk factors for developingatherosclerotic cardiovascular disease events include increasing age (65and over), male gender, a family history of atheroscleroticcardiovascular disease events, high blood cholesterol (especially LDL or“bad” cholesterol over 100 mg/dL), cigarette smoking and exposure totobacco smoke, high blood pressure, diabetes, obesity and physicalinactivity.

Also contemplated herein is the use of a compound of the invention, or apharmaceutically acceptable derivative thereof, in combination with oneor more of the following therapeutic agents in treating atherosclerosis:antihyperlipidemic agents, plasma HDL-raising agents,antihypercholesterolemic agents, cholesterol biosynthesis inhibitors(such as HMG CoA reductase inhibitors, such as lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin and rivastatin), acyl-coenzymeA:cholesterol acytransferase (ACAT) inhibitors, probucol, raloxifene,nicotinic acid, niacinamide, cholesterol absorption inhibitors, bileacid sequestrants (such as anion exchange resins, or quaternary amines(e.g., cholestyramine or colestipol)), low density lipoprotein receptorinducers, clofibrate, fenofibrate, benzafibrate, cipofibrate,gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidant vitamins, β-blockers,anti-diabetes agents, angiotensin II antagonists, angiotensin convertingenzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptorantagonists, aspirin or fibric acid derivatives.

In one embodiment compounds of the invention are used in combinationwith a cholesterol biosynthesis inhibitor, particularly an HMG-CoAreductase inhibitor. The term HMG-CoA reductase inhibitor is intended toinclude all pharmaceutically acceptable salt, ester, free acid andlactone forms of compounds which have HMG-CoA reductase inhibitoryactivity and, therefore, the use of such salts, esters, free acids andlactone forms is included within the scope of this invention. Compoundswhich have inhibitory activity for HMG-CoA reductase can be readilyidentified using assays well-known in the art. For instance, suitableassays are described or disclosed in U.S. Pat. No. 4,231,938 and WO84/02131. Examples of suitable HMG-CoA reductase inhibitors include, butare not limited to, lovastatin (MEVACOR®; see, U.S. Pat. No. 4,231,938);simvastatin (ZOCOR®; see, U.S. Pat. No. 4,444,784); pravastatin sodium(PRAVACHOL®); see, U.S. Pat. No. 4,346,227); fluvastatin sodium(LESCOL®); see, U.S. Pat. No. 5,354,772); atorvastatin calcium(LIPITOR®; see, U.S. Pat. No. 5,273,995) and rivastatin (also known ascerivastatin; see, U.S. Pat. No. 5,177,080). The structural formulas ofthese and additional HMG-CoA reductase inhibitors that can be used incombination with the compounds of the invention are described at page 87of M. Yalpani, “Cholesterol Lowering Drugs,” Chemistry & Industry, pp.85-89 (5 Feb. 1996). In presently preferred embodiments, the HMG-CoAreductase inhibitor is selected from lovastatin and simvastatin.

The compounds of the present invention can also be used in methods fordecreasing hyperglycemia and insulin resistance, i.e., in methods fortreating diabetes (International Patent Application Publication No. WO01/82917), and in methods of treatment, prevention, or amelioration ofdisorders related to, or arising as complications of diabetes,hyperglycemia or insulin resistance including the cluster of diseasestates, conditions or disorders that make up “Syndrome X” (See US PatentApplication 20030073614) comprising the administration of atherapeutically effective amount of a compound or composition of thepresent invention to a patient in need of such treatment.

Additionally the instant invention also provides a method for preventingor reducing the risk of developing hyperglycemia, insulin resistance,diabetes or syndrome X in a patient, comprising the administration of aprophylactically effective amount of a compound or composition of thepresent invention to a patient at risk for such an event.

Diabetes mellitus, commonly called diabetes, refers to a disease processderived from multiple causative factors and characterized by elevatedlevels of plasma glucose, referred to as hyperglycemia. See, e.g.,LeRoith, D. et al., (eds.), DIABETES MELLITUS (Lippincott-RavenPublishers, Philadelphia, Pa. U.S.A. 1996). According to the AmericanDiabetes Association, diabetes mellitus is estimated to affectapproximately 6% of the world population. Uncontrolled hyperglycemia isassociated with increased and premature mortality due to an increasedrisk for macrovascular and macrovascular diseases, includingnephropathy, neuropathy, retinopathy, hypertension, cerebrovasculardisease and coronary heart disease. Therefore, control of glucosehomeostasis is a critically important approach for the treatment ofdiabetes.

There are two major forms of diabetes: type 1 diabetes (formerlyreferred to as insulin-dependent diabetes or IDEM); and type 2 diabetes(formerly referred to as noninsulin dependent diabetes or NIDDM).

Type 2 diabetes is a disease characterized by insulin resistanceaccompanied by relative, rather than absolute, insulin deficiency. Type2 diabetes can range from predominant insulin resistance with relativeinsulin deficiency to predominant insulin deficiency with some insulinresistance. Insulin resistance is the diminished ability of insulin toexert its biological action across a broad range of concentrations. Ininsulin resistant individuals, the body secretes abnormally high amountsof insulin to compensate for this defect. When inadequate amounts ofinsulin are present to compensate for insulin resistance and adequatecontrol of glucose, a state of impaired glucose tolerance develops. In asignificant number of individuals, insulin secretion declines furtherand the plasma glucose level rises, resulting in the clinical state ofdiabetes. Type 2 diabetes can be due to a profound resistance to insulinstimulating regulatory effects on glucose and lipid metabolism in themain insulin-sensitive tissues: muscle, liver and adipose tissue. Thisresistance to insulin responsiveness results in insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver. In Type 2 diabetes, freefatty acid levels are often elevated in obese and some non-obesepatients and lipid oxidation is increased.

Premature development of atherosclerosis and increased rate ofcardiovascular and peripheral vascular diseases are characteristicfeatures of patients with diabetes. Hyperlipidemia is an importantprecipitating factor for these diseases. Hyperlipidemia is a conditiongenerally characterized by an abnormal increase in serum lipids, e.g.,cholesterol and triglyceride, in the bloodstream and is an importantrisk factor in developing atherosclerosis and heart disease. For areview of disorders of lipid metabolism, see, e.g., Wilson, J. et al.,(ed.), Disorders of Lipid Metabolism, Chapter 23, Textbook ofEndocrinology, 9th Edition, (W. B. Sanders Company, Philadelphia, Pa.U.S.A. 1998). Hyperlipidemia is usually classified as primary orsecondary hyperlipidemia. Primary hyperlipidemia is generally caused bygenetic defects, while secondary hyperlipidemia is generally caused byother factors, such as various disease states, drugs, and dietaryfactors. Alternatively, hyperlipidemia can result from both acombination of primary and secondary causes of hyperlipidemia. Elevatedcholesterol levels are associated with a number of disease states,including coronary artery disease, angina pectoris, carotid arterydisease, strokes, cerebral arteriosclerosis, and xanthoma.

Dyslipidemia, or abnormal levels of lipoproteins in blood plasma, is afrequent occurrence among diabetics, and has been shown to be one of themain contributors to the increased incidence of coronary events anddeaths among diabetic subjects (see, e.g., Joslin, E. Ann. Chim. Med.(1927), Vol. 5, pp. 1061-1079). Epidemiological studies since then haveconfirmed the association and have shown a several-fold increase incoronary deaths among diabetic subjects when compared with non-diabeticsubjects (see, e.g., Garcia, M. J. et al., Diabetes (1974), Vol. 23, pp.105-11 (1974); and Laakso, M. and Lehto, S., Diabetes Reviews (1997),Vol. 5, No. 4, pp. 294-315). Several lipoprotein abnormalities have beendescribed among diabetic subjects (Howard B., et al., Arteriosclerosis(1978), Vol. 30, pp. 153-162).

The compounds of the invention can also be used effectively incombination with one or more additional active diabetes agents dependingon the desired target therapy (see, e.g., Turner, N. et al., Prog. DrugRes. (1998), Vol. 51, pp. 33-94; Haffner, S., Diabetes Care (1998), Vol.21, pp. 160-178; and DeFronzo, R. et al. (eds.), Diabetes Reviews(1997), Vol. 5, No. 4). A number of studies have investigated thebenefits of combination therapies with oral agents (see, e.g., Mahler,R., J. Clin. Endocrinol. Metab. (1999), Vol. 84, pp. 1165-71; UnitedKingdom Prospective Diabetes Study Group: UKPDS 28, Diabetes Care(1998), Vol. 21, pp. 87-92; Bardin, C. W. (ed.), CURRENT THERAPY INENDOCRINOLOGY AND METABOLISM, 6th Edition (Mosby—Year Book, Inc., St.Louis, Mo. 1997); Chiasson, J. et al., Ann. Intern. Med. (1994), Vol.121, pp. 928-935; Coniff, R. et al., Clin. Ther. (1997), Vol. 19, pp.16-26; Coniff, R. et al., Am. J. Med. (1995), Vol. 98, pp. 443-451;Iwamoto, Y. et al., Diabet. Med. (1996), Vol. 13, pp. 365-370;Kwiterovich, P., Am. J. Cardiol (1998), Vol. 82 (12A), pp. 3U-17U).These studies indicate that diabetes and hyperlipidemia modulation canbe further improved by the addition of a second agent to the therapeuticregimen.

Accordingly, the compounds of the invention may be used in combinationwith one or more of the following therapeutic agents in treatingdiabetes: sulfonylureas (such as chlorpropamide, tolbutamide,acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride,and glipizide), biguanides (such as metformin), thiazolidinediones (suchas ciglitazone, pioglitazone, troglitazone, and rosiglitazone), andrelated insulin sensitizers, such as selective and non-selectiveactivators of PPARα, PPARβ and PPARγ; dehydroepiandrosterone (alsoreferred to as DHEA or its conjugated sulphate ester, DHEA-SO₄);antiglucocorticoids; TNFα inhibitors; α-glucosidase inhibitors (such asacarbose, miglitol, and voglibose), pramlintide (a synthetic analog ofthe human hormone amylin), other insulin secretagogues (such asrepaglinide, gliquidone, and nateglinide), insulin, as well as thetherapeutic agents discussed above for treating atherosclerosis.

Further provided by this invention are methods of using the compounds ofthe invention to treat obesity, as well as the complications of obesity.Obesity is linked to a variety of medical conditions including diabetesand hyperlipidemia. Obesity is also a known risk factor for thedevelopment of type 2 diabetes (See, e.g., Barrett-Conner, E., Epidemol.Rev. (1989), Vol. 11, pp. 172-181; and Knowler, et al., Am. J. Clin.Nutr. (1991), Vol. 53, pp. 1543-1551).

In addition, the compounds of the invention can be used in combinationwith agents used in treated obesity or obesity-related disorders. Suchagents, include, but are not limited to, phenylpropanolamine,phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine,pheniramine, β₃ adrenoceptor agonist agents; sibutramine,gastrointestinal lipase inhibitors (such as orlistat), and leptins.Other agents used in treating obesity or obesity-related disordersinclude neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin,histamine H₃ receptors, dopamine D₂ receptor modulators, melanocytestimulating hormone, corticotrophin releasing factor, galanin and gammaamino butyric acid (GABA).

Evaluation of the Utility of the Compounds of the Invention

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possessbiological activities that modulate the activity or nuclear receptors,including the LXRs (LXRα and LXRβ). Such assays include, for example,biochemical assays such as binding assays, fluorescence polarizationassays, FRET based coactivator recruitment assays (see, generally,Glickman et al., J. Biomolecular Screening (2002), Vol. 7, No. 1, pp.3-10, as well as cell based assays including the co-transfection assay,the use of LBD-Gal 4 chimeras and protein-protein interaction assays,(see, Lehmann. et al., J. Biol. Chem. (1997), Vol. 272, No. 6, pp.3137-3140.

High throughput screening systems are commercially available (see, e.g.,Zymark Corp., Hopkinton, Mass.; Air Technical Industries, Mentor, Ohio;Beckman Instruments Inc., Fullerton, Calif.; Precision Systems, Inc.,Natick, Mass.) that enable these assays to be run in a high throughputmode. These systems typically automate entire procedures, including allsample and reagent pipetting, liquid dispensing timed incubations, andfinal readings of the microplate in detector(s) appropriate for theassay. These configurable systems provide high throughput and rapidstart up as well as a high degree of flexibility and customization. Themanufacturers of such systems provide detailed protocols for varioushigh throughput systems. Thus, for example, Zymark Corp. providestechnical bulletins describing screening systems for detecting themodulation of gene transcription, ligand binding, and the like.

Assays that do not require washing or liquid separation steps arepreferred for such high throughput screening systems and includebiochemical assays such as fluorescence polarization assays (see, forexample, Owicki, J., Biomol. Screen (2000 October), Vol. 5, No. 5, pp.297), scintillation proximity assays (SPA) (see, for example, Carpenteret al., Methods Mol. Biol. (2002), Vol 190, pp. 31-49) and fluorescenceresonance energy transfer energy transfer (FRET) or time resolved FRETbased coactivator recruitment assays (Mukherjee et al., J. SteroidBiochem. Mol. Biol. (2002 July); Vol. 81, No. 3, pp. 217-25; (Zhou etal., Mol. Endocrinol. (1998 October), Vol. 12, No. 10, pp. 1594-604).Generally such assays can be preformed using either the full lengthreceptor, or isolated ligand binding domain (LBD). In the case of LXRα,the LBD comprises amino acids 188-447, for LXRβ the LDB comprises aminoacids 198-461, and for FXR, the LBD comprises amino acids 244 to 472 ofthe full length sequence.

If a fluorescently labeled ligand is available, fluorescencepolarization assays provide a way of detecting binding of compounds tothe nuclear receptor of interest by measuring changes in fluorescencepolarization that occur as a result of the displacement of a traceamount of the label ligand by the compound. Additionally this approachcan also be used to monitor the ligand dependent association of afluorescently labeled coactivator peptide to the nuclear receptor ofinterest to detect ligand binding to the nuclear receptor of interest.

The ability of a compound to bind to a receptor, or heterodimer complexwith RXR, can also be measured in a homogeneous assay format byassessing the degree to which the compound can compete off aradiolabelled ligand with known affinity for the receptor using ascintillation proximity assay (SPA). In this approach, the radioactivityemitted by a radiolabelled compound (for example, [³H] 24,25Epoxycholesterol) generates an optical signal when it is brought intoclose proximity to a scintillant such as a Ysi-copper containing bead,to which the nuclear receptor is bound. If the radiolabelled compound isdisplaced from the nuclear receptor the amount of light emitted from thenuclear receptor bound scintillant decreases, and this can be readilydetected using standard microplate liquid scintillation plate readerssuch as, for example, a Wallac MicroBeta reader.

The heterodimerization of LXR with RXRα can also be measured byfluorescence resonance energy transfer (FRET), or time resolved FRET, tomonitor the ability of the compounds provided herein to bind to LXR orother nuclear receptors. Both approaches rely upon the fact that energytransfer from a donor molecule to an acceptor molecule only occurs whendonor and acceptor are in close proximity. Typically the purified LBD ofthe nuclear receptor of interest is labeled with biotin then mixed withstoichiometric amounts of europium labeled streptavidin (Wallac Inc.),and the purified LBD of RXRα is labeled with a suitable fluorophore suchas CY5™. Equimolar amounts of each modified LBD are mixed together andallowed to equilibrate for at least 1 hour prior to addition to eithervariable or constant concentrations of the sample for which the affinityis to be determined. After equilibration, the time-resolved fluorescentsignal is quantitated using a fluorescent plate reader. The affinity ofthe compound can then be estimated from a plot of fluorescence versusconcentration of compound added.

This approach can also be exploited to measure the ligand dependentinteraction of a co-activator peptide with a nuclear receptor in orderto characterize the agonist or antagonist activity of the compoundsdisclosed herein. Typically the assay in this case involves the use arecombinant Glutathione-S-transferase (GST)-nuclear receptor ligandbinding domain (LBD) fusion protein and a synthetic biotinylated peptidesequenced derived from the receptor interacting domain of a co-activatorpeptide such as the steroid receptor coactivator 1 (SRC-1). TypicallyGST-LBD is labeled with a europium chelate (donor) via a europium-taggedanti-GST antibody, and the coactivator peptide is labeled withallophycocyanin via a streptavidin-biotin linkage.

In the presence of an agonist for the nuclear receptor, the peptide isrecruited to the GST-LBD bringing europium and allophycocyanin intoclose proximity to enable energy transfer from the europium chelate tothe allophycocyanin. Upon excitation of the complex with light at 340 nmexcitation energy absorbed by the europium chelate is transmitted to theallophycocyanin moiety resulting in emission at 665 nm. If the europiumchelate is not brought in to close proximity to the allophycocyaninmoiety there is little or no energy transfer and excitation of theeuropium chelate results in emission at 615 nm. Thus the intensity oflight emitted at 665 nm gives an indication of the strength of theprotein-protein interaction. The activity of a nuclear receptorantagonist can be measured by determining the ability of a compound tocompetitively inhibit (i.e., IC₅₀) the activity of an agonist for thenuclear receptor.

In addition a variety of cell based assay methodologies may besuccessfully used in screening assays to identify and profile thespecificity of compounds of the present invention. These approachesinclude the co-transfection assay, translocation assays, complementationassays and the use of gene activation technologies to over expressendogenous nuclear receptors.

Three basic variants of the co-transfection assay strategy exist,co-transfection assays using full-length nuclear receptor, cotransfection assays using chimeric nuclear receptors comprising theligand binding domain of the nuclear receptor of interest fused to aheterologous DNA binding domain, and assays based around the use of themammalian two hybrid assay system.

The basic co-transfection assay is based on the co-transfection into thecell of an expression plasmid to express the nuclear receptor ofinterest in the cell with a reporter plasmid comprising a reporter genewhose expression is under the control of DNA sequence that is capable ofinteracting with that nuclear receptor (see, for example, U.S. Pat. Nos.5,071,773; 5,298,429 and 6,416,957). Treatment of the transfected cellswith an agonist for the nuclear receptor increases the transcriptionalactivity of that receptor which is reflected by an increase inexpression of the reporter gene which may be measured by a variety ofstandard procedures.

For those receptors that function as heterodimers with RXR, such as theLXRs, the co-transfection assay typically includes the use of expressionplasmids for both the nuclear receptor of interest and RXR. Typicalco-transfection assays require access to the full length nuclearreceptor and suitable response elements that provide sufficientscreening sensitivity and specificity to the nuclear receptor ofinterest.

Typically, the expression plasmid comprises: (1) a promoter, such as anSV40 early region promoter, HSV tk promoter or phosphoglycerate kinase(pgk) promoter, CMV promoter, Srα promoter or other suitable controlelements known in the art, (2) a cloned polynucleotide sequence, such asa cDNA encoding a receptor, co-factor, or fragment thereof, ligated tothe promoter in sense orientation so that transcription from thepromoter will produce a RNA that encodes a functional protein, and (3) apolyadenylation sequence. For example and not limitation, an expressioncassette of the invention may comprise the cDNA expression cloningvectors, or other preferred expression vectors known and commerciallyavailable from vendors such as Invitrogen, (CA), Stratagene, (CA) orClontech, (CA). Alternatively expression vectors developed by academicgroups such as the pCMX vectors originally developed in the Evans lab(Willey et al. Genes & Development 9 1033-1045 (1995)) may also be used.

The transcriptional regulatory sequences in an expression cassette areselected by the practitioner based on the intended application;depending upon the specific use, transcription regulation can employinducible, repressible, constitutive, cell-type specific, developmentalstage-specific, sex-specific, or other desired type of promoter orcontrol sequence.

Alternatively, the expression plasmid may comprise an activationsequence to activate or increase the expression of an endogenouschromosomal sequence. Such activation sequences include for example, asynthetic zinc finger motif (for example see U.S. Pat. Nos. 6,534,261and 6,503,7171) or a strong promoter or enhancer sequence together witha targeting sequence to enable homologous or non-homologousrecombination of the activating sequence upstream of the gene ofinterest.

Genes encoding the following full-length previously described proteins,which are suitable for use in the co-transfection studies and profilingthe compounds described herein, include human LXR α (accession U22662)(SEQ ID NOS: 5-6), human LXR β (accession U07132) (SEQ ID NOS: 11-12),rat FXR (accession U18374) (SEQ ID NOS: 13-14), human FXR (accessionNM_(—)005123) (SEQ ID NOS: 15-16), human RXR α (accession NM_(—)002957)(SEQ ID NO: 17-18), human RXR β (accession XM_(—)042579) (SEQ ID NOS:19-20), human RXR γ (accession XM_(—)053680) (SEQ ID NOS: 21-22), humanPPARα (accession X57638) (SEQ ID NOS: 23-24) and human PPAR δ (accessionU10375) (SEQ ID NOS: 25-26). All accession numbers in this applicationrefer to GenBank accession numbers.

Reporter plasmids may be constructed using standard molecular biologicaltechniques by placing cDNA encoding for the reporter gene downstreamfrom a suitable minimal promoter. For example luciferase reporterplasmids may be constructed by placing cDNA encoding firefly luciferase(typically with SV40 small t intron and poly-A tail, (de Wet et al.,(1987) Mol. Cell. Biol. 7 725-735) down stream from the herpes virusthymidine kinase promoter (located at nucleotides residues-105 to +51 ofthe thymidine kinase nucleotide sequence, obtained for example, from theplasmid pBLCAT2 (Luckow & Schutz (1987) Nucl. Acid. Res. 15 5490-5494))which is linked in turn to the appropriate response element (RE).

The choice of hormone response element is dependent upon the type ofassay to be used. In the case of the use of the full-length LXR α or LXRβ a reporter plasmid comprising a known LXR RE would typically be used,such as for example in a reporter plasmid such as LXREx1-tk-luciferase,(see U.S. Pat. No. 5,747,661, which is hereby incorporated byreference). In the case of a LXR a or LXR P-LBD-Gal4 fusion, GAL4Upstream Activating Sequences (UAS) would be used. Typically the GAL4UAS would comprise the sequence 5′CGGRNNRCYNYNCNCCG-3′ (SEQ ID NO: 27),where Y=C or T, R=A or G, and N=A, C, T or G, and would be present as atandem repeat of 4 copies.

Numerous methods of co-transfecting the expression and reporter plasmidsare known to those of skill in the art and may be used for theco-transfection assay to introduce the plasmids into a suitable celltype. Typically such a cell will not endogenously express nuclearreceptors that interact with the response elements used in the reporterplasmid.

Numerous reporter gene systems are known in the art and include, forexample, alkaline phosphatase (see, Berger, J., et al., Gene (1988),Vol. 66, pp. 1-10; and Kain, S. R., Methods. Mol. Biol. (1997), Vol. 63,pp. 49-60), β-galactosidase (See, U.S. Pat. No. 5,070,012, issued Dec.,3, 1991 to Nolan et al., and Bronstein, I., et al., J. Chemilum. Biolum.(1989), Vol. 4, pp. 99-111), chloramphenicol acetyltransferase (See,Gorman et al., Mol. Cell. Biol. (1982), Vol. 2, pp. 1044-51),β-glucuronidase, peroxidase, β-lactamase (U.S. Pat. Nos. 5,741,657 and5,955,604), catalytic antibodies, luciferases (U.S. Pat. Nos. 5,221,623;5,683,888; 5,674,713; 5,650,289; and 5,843,746) and naturallyfluorescent proteins (Tsien, R. Y., Annu. Rev. Biochem. (1998), Vol. 67,pp. 509-44).

The use of chimeras comprising the ligand binding domain (LBD) of thenuclear receptor of interest to a heterologous DNA binding domain (DBD)expands the versatility of cell based assays by directing activation ofthe nuclear receptor in question to defined DNA binding elementsrecognized by defined DNA binding domain (see WO95/18380). This assayexpands the utility of cell based co-transfection assays in cases wherethe biological response or screening window using the native DNA bindingdomain is not satisfactory.

In general the methodology is similar to that used with the basicco-transfection assay, except that a chimeric construct is used in placeof the full length nuclear receptor. As with the full length nuclearreceptor, treatment of the transfected cells with an agonist for thenuclear receptor LBD increases the transcriptional activity of theheterologous DNA binding domain which is reflected by an increase inexpression of the reporter gene as described above. Typically for suchchimeric constructs, the DNA binding domains from defined nuclearreceptors, or from yeast or bacterially derived transcriptionalregulators such as members of the GAL 4 and Lex A/Umud super familiesare used.

A third cell based assay of utility for screening compounds of thepresent invention is a mammalian two-hybrid assay that measures theability of the nuclear hormone receptor to interact with a cofactor inthe presence of a ligand (see, for example, U.S. Pat. Nos. 5,667,973,5,283,173 and 5,468,614). The basic approach is to create three plasmidconstructs that enable the interaction of the nuclear receptor with theinteracting protein to be coupled to a transcriptional readout within aliving cell. The first construct is an expression plasmid for expressinga fusion protein comprising the interacting protein, or a portion ofthat protein containing the interacting domain, fused to a GAL4 DNAbinding domain. The second expression plasmid comprises DNA encoding thenuclear receptor of interest fused to a strong transcription activationdomain such as VP16, and the third construct comprises the reporterplasmid comprising a reporter gene with a minimal promoter and GAL4upstream activating sequences.

Once all three plasmids are introduced into a cell, the GAL4 DNA bindingdomain encoded in the first construct allows for specific binding of thefusion protein to GAL4 sites upstream of a minimal promoter. Howeverbecause the GAL4 DNA binding domain typically has no strongtranscriptional activation properties in isolation, expression of thereporter gene occurs only at a low level. In the presence of a ligand,the nuclear receptor-VP16 fusion protein can bind to theGAL4-interacting protein fusion protein bringing the strongtranscriptional activator VP16 in close proximity to the GAL4 bindingsites and minimal promoter region of the reporter gene. This interactionsignificantly enhances the transcription of the reporter gene which canbe measured for various reporter genes as described above. Transcriptionof the reporter gene is thus driven by the interaction of theinteracting protein and nuclear receptor of interest in a liganddependent fashion.

Any compound which is a candidate for activation of LXRα or LXRβ may betested by these methods. Generally, compounds are tested at severaldifferent concentrations to optimize the chances that activation of thereceptor will be detected and recognized if present. Typically assaysare performed in triplicate and vary within experimental error by lessthan 15%. Each experiment is typically repeated three or more times withsimilar results.

Activity of the reporter gene can be conveniently normalized to theinternal control and the data plotted as fold activation relative tountreated cells. A positive control compound (agonist) may be includedalong with DMSO as high and low controls for normalization of the assaydata. Similarly, antagonist activity can be measured by determining theability of a compound to competitively inhibit the activity of anagonist.

Additionally the compounds and compositions can be evaluated for theirability to increase or decrease the expression of genes known to bemodulated by LXRα or LXRβ and other nuclear receptors in vivo, usingNorthern-blot, RT PCR or oligonucleotide microarray analysis to analyzeRNA levels. Western-blot analysis can be used to measure expression ofproteins encoded by LXR target genes. Genes that are known to beregulated by the LXRs include the ATP binding cassette transportersABCA1, ABCG1, ABCG5, ABCG8, the sterol response element binding protein1c (SREBP1c) gene, stearoyl CoA desaturase 1 (SCD-1) and theapolipoprotein apoE gene (ApoE).

Established animal models exist for a number of diseases of directrelevance to the claimed compounds and these can be used to furtherprofile and characterize the claimed compounds. These model systemsinclude diabetic dyslipidemia using Zucker (fa/fa) rats or (db/db) mice,spontaneous hyperlipidemia using apolipoprotein E deficient mice(ApoE^(−/−)), diet-induced hyperlipidemia, using low density lipoproteinreceptor deficient mice (LDR^(−/−)) and atherosclerosis using both theApo E(^(−/−)) and LDL(^(−/−)) mice fed a western diet. (21% fat, 0.05%cholesterol). Additionally LXR or FXR animal models (e.g., knockoutmice) can be used to further evaluate the present compounds andcompositions in vivo (see, for example, Peet, et al., Cell (1998), Vol.93, pp. 693-704, and Sinal, et al., Cell (2000), Vol. 102, pp. 731-744).

Administration of the Compounds of the Invention

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques. Pharmaceutical compositions of the invention are formulatedso as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington's PharmaceuticalSciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). Thecomposition to be administered will, in any event, contain atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof, for treatment of adisease-state associated with the activity of a nuclear receptor inaccordance with the teachings of this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, e.g.,inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, e.g., agelatin capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, e.g., anelixir, syrup, solution, emulsion or suspension. The liquid may be fororal administration or for delivery by injection, as two examples. Whenintended for oral administration, preferred composition contain, inaddition to the present compounds, one or more of a sweetening agent,preservatives, dye/colorant and flavor enhancer. In a compositionintended to be administered by injection, one or more of a surfactant,preservative, wetting agent, dispersing agent, suspending agent, buffer,stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the inventionin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 50% of the compound of the invention. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 1% by weight of the compound of the invention.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the invention from about 0.1 to about10% w/v (weight per unit volume).

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, e.g., of a suppository, which willmelt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy. Generally, atherapeutically effective daily dose is from about 0.1 mg to about 20mg/kg of body weight per day of a compound of the invention, or apharmaceutically acceptable salt thereof; preferably, from about 0.1 mgto about 10 mg/kg of body weight per day; and most preferably, fromabout 0.1 mg to about 7.5 mg/kg of body weight per day.

Compounds of the invention, or pharmaceutically acceptable derivativesthereof, may also be administered simultaneously with, prior to, orafter administration of one or more of the therapeutic agents describedabove in the Utility of the Compounds of the Invention. Such combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of the invention and one or moreadditional active agents, as well as administration of the compound ofthe invention and each active agent in its own separate pharmaceuticaldosage formulation. For example, a compound of the invention and anHMG-CoA reductase inhibitor can be administered to the patient togetherin a single oral dosage composition such as a tablet or capsule, or eachagent administered in separate oral dosage formulations. Where separatedosage formulations are used, the compounds of the invention and one ormore additional active agents can be administered at essentially thesame time, i.e., concurrently, or at separately staggered times, i.e.,sequentially; combination therapy is understood to include all theseregimens.

Dosage information for HMG-CoA reductase inhibitors is well known in theart, since several HMG-CoA reductase inhibitors are marketed in the U.S.In particular, the daily dosage amounts of the HMG-CoA reductaseinhibitor may be the same or similar to those amounts which are employedfor anti-hypercholesterolemic treatment and which are described in thePhysicians' Desk Reference (PDR). For example, see the 50th Ed. of thePDR, 1996 (Medical Economics Co); in particular, see at page 216 theheading “Hypolipidemics,” sub-heading “HMG-CoA Reductase Inhibitors,”and the reference pages cited therein. Preferably, the oral dosageamount of HMG-CoA reductase inhibitor is from about 1 to 200 mg/day and,more preferably, from about 5 to 160 mg/day. However, dosage amountswill vary depending on the potency of the specific HMG-CoA reductaseinhibitor used as well as other factors as noted above. An HMG-CoAreductase inhibitor which has sufficiently greater potency may be givenin sub-milligram daily dosages.

As examples, the daily dosage amount for simvastatin may be selectedfrom 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg for lovastatin, 10 mg,20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg;and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The daily dosageamount for atorvastatin calcium may be in the range of from 1 mg to 160mg and, more particularly, from 5 mg to 80 mg. Oral administration maybe in a single or divided doses of two, three, or four times daily,although a single daily dose of the HMG-CoA reductase inhibitor ispreferred.

Embodiments of the Compounds of the Invention

One embodiment of the compounds of formula (I), as set forth above inthe Summary of the Invention, is that group of compounds having thefollowing formula (II):

wherein n is 1 to 4; m is 1 to 4; R¹ is hydrogen, aralkyl orheteroarylalkyl; R² is hydrogen, cyano or —R⁷—N(R⁸)₂; R³ is hydrogen orhaloalkyl; each R⁴ is independently hydrogen, halo, alkyl or haloalkyl;each R⁵ is independently selected from the group consisting of hydrogen,halo, nitro, alkyl, alkenyl, aryl, aralkyl, aralkenyl, haloalkyl,haloalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R⁷—CN, —R⁷—N(R⁸)₂,—R⁷—OR⁸, —R⁷—O—R⁹—C(O)OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂,—R⁷—C(O)N(R⁸)OR⁸, —R⁷—C(O)N(R⁸)N(R⁸)₂, —R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸,—R⁷—C(S)N(R⁸)₂, —R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—S(O)_(t)R⁸ (where t is 0 to 2)and —R⁷—S(O)₂N(R⁸)₂; R⁶ is —OR⁷—, a direct bond, a straight or branchedalkylene chain, a straight or branched alkenylene chain or a straight orbranched alkynylene chain; each R⁷ is independently selected from adirect bond, a straight or branched alkylene chain or a straight orbranched alkenylene chain; each R⁸ is independently selected fromhydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl,aralkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R⁹ is independently selected from astraight or branched alkylene chain or a straight or branched alkenylenechain; R¹⁰ is alkyl, aryl, aralkyl or cycloalkylalkyl; and R¹¹ ishydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heterarylalkyl; as anisomer, a mixture of stereoisomers, a racemic mixture thereof ofstereoisomers, or as a tautomer; or as a pharmaceutically acceptablesalt, prodrug, solvate or polymorph thereof.

Of this group of compounds, one embodiment is that subgroup of compoundswherein n is 1; m is 1 or 2; R¹ is aralkyl or heteroarylalkyl; R² iscyano; R³ is haloalkyl; R⁴ is hydrogen, halo, alkyl or haloalkyl; eachR⁵ is independently selected from the group consisting of hydrogen,halo, nitro, alkyl, alkenyl, haloalkyl, heterocyclyl, heteroaryl,—R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸, —R⁷—O—R⁹—C(O)OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸,—R⁷—C(O)N(R⁸)₂, —R⁷—C(O)N(R⁸)OR⁸, —R⁷—C(O)N(R⁸)N(R⁸)₂,—R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸, —R⁷—C(S)N(R⁸)₂, —R⁷—N(R⁸)C(O)OR¹⁰,—R⁷—S(O)_(t)R⁸ (where t is 0 to 2) and —R⁷—S(O)₂N(R⁸)₂; R⁶ is —OR⁷—, adirect bond, a straight or branched alkenylene chain or a straight orbranched alkynylene chain; each R⁷ is independently selected from adirect bond or a straight or branched alkylene chain; each R⁸ isindependently selected from hydrogen, alkyl, alkenyl, haloalkyl,haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R⁹is a straight or branched alkylene chain optionally substituted by arylor heteroaryl; R¹⁰ is alkyl, aryl, aralkyl or cycloalkylalkyl; and R¹¹is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heterarylalkyl.

Of this subgroup of compounds, one embodiment is that class of compoundswherein R⁶ is —OR⁷—.

Of this class of compounds, one embodiment is that subclass of compoundswherein R¹ is aralkyl optionally substituted with one or moresubstituents independently selected from alkyl, halo or haloalkyl.

Of this subclass of compounds, one embodiment is that set of compoundswherein n is 1; m is 1 or 2; R² is cyano; R³ is trifluoromethyl; R⁴ ishydrogen, methyl, 1-methylethyl or chloro; each R⁵ is independentlyselected from the group consisting of hydrogen, halo, alkyl, alkenyl orhaloalkyl.

Of this set of compounds, one embodiment is that subset of compoundswherein each R⁵ is independently selected from hydrogen, chloro, bromo,fluoro, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, ethenyl ortrifluoromethyl.

Of the subclass of compounds set forth above, another embodiment is thatset of compounds wherein n is 1; m is 1 or 2; R² is cyano; R³ istrifluoromethyl; R⁴ is hydrogen, methyl, 1-methylethyl or chloro; eachR⁵ is independently selected from the group consisting of haloalkyl,—R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸ and R⁷—O—R⁹—C(O)OR⁸ each R⁷ is independentlyselected from a direct bond or methylene chain; each R⁸ is independentlyselected from hydrogen, alkyl, aryl and aralkyl; and R⁹ is a methylenechain.

Of the subclass of compounds set forth above, another embodiment is thatset of compounds wherein n is 1; m is 1 or 2; R² is cyano; R³ istrifluoromethyl; R⁴ is hydrogen, methyl, 1-methylethyl or chloro; eachR⁵ is independently selected from the group consisting of heteroaryl,—R⁷—OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—C(O)N(R⁸)OR⁸,—R⁷—C(O)N(R⁸)N(R⁸)₂, —R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸, —R⁷—C(S)N(R⁸)₂ and—R⁷—S(O)_(t)R⁸ (where t is 0 to 2); each R⁷ is independently selectedfrom a direct bond or a straight or branched alkylene chain; each R⁸ isindependently selected from hydrogen, alkyl, haloalkyl, aryl, aralkyl,aralkenyl, cycloalkyl or heterocyclyl optionally substituted withhydroxy; R⁹ is a straight or branched alkylene chain (optionallysubstituted by phenyl or imidazolyl); and R¹¹ is hydrogen, alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heterarylalkyl.

Of this set of compounds, one embodiment is that subset of compoundswherein m is 1 or 2; each R⁵ is independently selected from —R⁷—OR⁸,—R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—C(O)N(R⁸)OR⁸ or—R⁷—C(O)N(R⁸)N(R⁸)₂; each R⁷ is independently selected from a directbond or methylene; each R⁸ is independently selected from hydrogen,methyl, ethyl, 1,1-dimethylethyl, benzyl, 2-phenylethyl, cyclohexyl orpiperidinyl optionally substituted by hydroxy; and R¹¹ is hydrogen,alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heterarylalkyl.

Of the subclass of compounds set forth above, another embodiment is thatset of compounds wherein n is 1; m is 1 or 2; R² is cyano; R³ istrifluoromethyl; R⁴ is hydrogen, methyl, 1-methylethyl or chloro; eachR⁵ is independently selected from the group consisting of heteroaryl,—R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸, —R⁷—C(S)N(R⁸)₂ and —R⁷—S(O)_(t)R⁸ (where t is0 to 2); each R⁷ is independently selected from a direct bond or astraight or branched alkylene chain; each R⁸ is independently selectedfrom hydrogen or alkyl, haloalkyl, aryl, aralkyl, aralkenyl, cycloalkylor heterocyclyl; and R⁹ is a straight or branched alkylene chain(optionally substituted by phenyl or imidazolyl).

Of this set of compounds, one embodiment is that subset of compoundswherein n is 1; m is 1; R² is cyano; R³ is trifluoromethyl; R⁴ ishydrogen or chloro; R⁵ is —R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸; R⁷ is a direct bond;each R⁸ is independently hydrogen or alkyl; and R⁹ is a straight orbranched alkylene chain optionally substituted by phenyl or imidazolyl.

Of this set of compounds, another embodiment is that subset of compoundswherein n is 1; m is 1; R² is cyano; R³ is trifluoromethyl; R⁴ ishydrogen, methyl, 1-methylethyl or chloro; each R⁵ is independentlyselected from the group consisting of phthalimidyl, —R⁷—C(S)N(R⁸)₂ and—R⁷—S(O)_(t)R⁸ (where t is 0 or 2); each R⁷ is a direct bond; and eachR⁸ is independently selected from hydrogen or alkyl.

Of the class of compounds of formula (II) as set forth above, anotherembodiment is that subclass of compounds wherein R¹ is heteroarylalkyl.

Of this subclass of compounds, one embodiment is that set of compoundswherein n is 1; m is 1 or 2; R¹ is optionally substitutedthiazol-5-ylmethyl; R² is cyano; R³ is trifluoromethyl; R⁴ is hydrogen,methyl, 1-methylethyl or chloro; each R⁵ is independently selected fromthe group consisting of hydrogen, halo, alkyl, alkenyl or haloalkyl.

Of the subgroup of compounds of formula (II) set forth above, anotherembodiment is that class of compounds wherein R¹ is aralkyl optionallysubstituted with one or more substituents independently selected fromalkyl, halo or haloalkyl; each R⁵ is independently selected from thegroup consisting of hydrogen, halo, nitro, alkyl, alkenyl, haloalkyl,—R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂,—R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—S(O)_(t)R⁸ (where t is 0 to 2) and—R⁷—S(O)₂N(R⁸)₂; R⁶ is a direct bond, a straight or branched alkenylenechain or a straight or branched alkynylene chain; each R⁷ isindependently selected from a direct bond or a straight or branchedalkylene chain; each R⁸ is independently selected from hydrogen, alkyl,cycloalkyl, cycloalkylalkyl or heterocyclyl; each R⁹ is a straight orbranched alkylene chain optionally substituted by aryl or heteroaryl;R¹⁰ is alkyl, aryl, aralkyl or cycloalkylalkyl; and R¹¹ is hydrogen,alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heterarylalkyl.

Of this class of compounds, one embodiment is that subclass of compoundswherein n is 1; m is 1 or 2; R¹ is benzyl optionally substituted withone or more substituents independently selected from alkyl, halo orhaloalkyl; R² is cyano; R³ is trifluoromethyl; R⁴ is hydrogen; each R⁵is independently selected from the group consisting of alkyl,trifluoromethyl, —R⁷—OR⁸ and R⁷—S(O)_(t)R⁸ (where t is 0 to 2); R⁶ is adirect bond; R⁷ is a direct bond; R⁸ is hydrogen or alkyl; and R⁹ is astraight or branched alkylene chain.

Of this class of compound, another embodiment is that subclass ofcompounds wherein n is 1; m is 1 or 2; R¹ is benzyl optionallysubstituted with one or more substituents independently selected fromalkyl, halo or haloalkyl; R² is cyano; R³ is trifluoromethyl; R⁴ ishydrogen; each R⁵ is independently selected from the group consisting ofalkyl, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸ or —R⁷—C(O)N(R⁸)₂; R⁶ is a direct bond;each R⁷ is a direct bond; each R⁸ is independently hydrogen, alkyl, arylor aralkyl; and R¹¹ is hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, pyrrolidinyl orpiperidinyl.

Of this class of compound, another embodiment is that subclass ofcompounds wherein n is 1; m is 1 or 2; R² is cyano; R³ istrifluoromethyl; R⁴ is hydrogen; each R⁵ is independently selected fromthe group consisting of hydrogen, halo, alkyl, alkenyl, haloalkyl or—R⁷—OR⁸; R⁶ is a direct bond, a straight or branched alkenylene chain ora straight or branched alkynylene chain; R⁷ is a direct bond; and R⁸ ishydrogen or alkyl.

Of this class of compound, another embodiment is that subclass ofcompounds wherein n is 1; m is 1 or 2; R² is cyano; R³ istrifluoromethyl; R⁴ is hydrogen; each R⁵ is independently selected fromthe group consisting of nitro, —R⁷—N(R⁸)₂, —R⁷—OR⁸ or —R⁷—N(R⁸)C(O)OR¹⁰;R⁶ is a direct bond; each R⁷ is a direct bond; each R⁸ is independentlyselected from hydrogen or alkyl; and R¹⁰ is alkyl.

Another embodiment of the compounds of formula (I), as set forth abovein the Summary of the Invention, is that group of compounds having thefollowing formula (III):

wherein Y is oxygen or sulfur; n is 1 or 2; m is 1 to 4; R¹ is aralkyl;R² is hydrogen, cyano, —R⁷—N(R⁸)₂, —R⁷—N(R⁸)S(O)₂R¹⁰ or—R⁷—N(R⁸)C(NR⁸)N(R⁸)₂; R³ is hydrogen or haloalkyl; each R⁴ isindependently hydrogen, halo, alkyl or haloalkyl; each R⁵ isindependently selected from the group consisting of hydrogen, halo,nitro, alkyl, alkenyl, aryl, aralkyl, aralkenyl, haloalkyl, haloalkenyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸, —R⁷—OC(O)OR⁸,—R⁷—O—R⁹—C(O)OR⁸, —R⁷—O—R⁹—OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸,—R⁷—C(O)N(R⁸)₂, —R⁷—C(O)N(R⁸)OR⁸, —R⁷—C(O)N(R⁸)N(R⁸)₂,—R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸, —R⁷—C(S)N(R⁸)₂, —R⁷—N(R⁸)C(O)OR¹⁰,—R⁷—S(O)_(t)R⁸ (where t is 0 to 2) and —R⁷—S(O)₂N(R⁸)₂; R⁶ is —N(R⁸)—, adirect bond, a straight or branched alkylene chain, a straight orbranched alkenylene chain or a straight or branched alkynylene chain;each R⁷ is independently selected from a direct bond, a straight orbranched alkylene chain or a straight or branched alkenylene chain; eachR⁸ is independently selected from hydrogen, alkyl, alkenyl, haloalkyl,haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R⁹is independently selected from a straight or branched alkylene chain ora straight or branched alkenylene chain; each R¹⁰ is independentlyselected from alkyl, aryl, aralkyl or cycloalkylalkyl; and R¹¹ ishydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heterarylalkyl; as anisomer, a mixture of stereoisomers, a racemic mixture thereof ofstereoisomers, or as a tautomer; or as a pharmaceutically acceptablesalt, prodrug, solvate or polymorph thereof.

Of this group of compounds, one embodiment is that subgroup of compoundswherein Y is oxygen or sulfur; n is 1 or 2; m is 1 to 4; R¹ is aralkyloptionally substituted with one or more substituents selected from thegroup consisting of alkyl and halo; R² is hydrogen, cyano, —R⁷—N(R⁸)₂,—R⁷—N(R⁸)S(O)₂R¹⁰ or —R⁷—N(R⁸)C(NR⁸)N(R⁸)₂; R³ is hydrogen or haloalkyl;each R⁴ is independently hydrogen, halo, alkyl or haloalkyl; each R⁵ isindependently selected from the group consisting of hydrogen, halo,nitro, alkyl, haloalkyl, —R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸, —R⁷—OC(O)OR⁸,—R⁷—O—R⁹—C(O)OR⁸, —R⁷—O—R⁹—OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸,—R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—S(O)_(t)R⁸ (where t is 0 to 2) and—R⁷—S(O)₂N(R⁸)₂; R⁶ is —N(R⁸)—, a direct bond, a straight or branchedalkylene chain, a straight or branched alkenylene chain or a straight orbranched alkynylene chain; each R⁷ is independently selected from adirect bond or a straight or branched alkylene chain; each R⁸ isindependently selected from hydrogen, alkyl, alkenyl, haloalkyl,haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R⁹is a straight or branched alkylene chain; each R¹⁰ is independentlyselected from alkyl, aryl, aralkyl or cycloalkylalkyl; and R¹¹ ishydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heterarylalkyl.

Of this subgroup of compounds, one embodiment is that class of compoundswherein Y is sulfur.

Of this class of compounds, one embodiment is that subclass of compoundswherein n is 1; m is 1 to 3; R¹ is benzyl optionally substituted withone or more substituents selected from the group consisting of chloro,bromo, fluoro, methyl or ethyl; R² is hydrogen, cyano, —R⁷—N(R⁸)₂,—R⁷—N(R⁸)S(O)₂R¹⁰ or —R⁷—N(R⁸)C(NR⁸)N(R⁸)₂; R³ is haloalkyl; R⁴ ishydrogen; each R⁵ is independently selected from the group consisting ofhydrogen, halo, nitro, alkyl, haloalkyl, —R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸,—R⁷—OC(O)OR⁸, —R⁷—O—R⁹—C(O)O R⁸, —R⁷—O—R⁹—OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸,—R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—S(O)_(t)R⁸ (where t is 0 to 2) and—R⁷—S(O)₂N(R⁸)₂; R⁶ is a direct bond, a straight or branched alkylenechain, a straight or branched alkenylene chain or a straight or branchedalkynylene chain; each R⁷ is independently selected from a direct bondor a straight or branched alkylene chain; each R⁸ is independentlyselected from hydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl,aralkyl, aralkenyl, cycloalkyl or cycloalkylalkyl; each R⁹ is a straightor branched alkylene chain; each R¹⁰ is independently selected fromalkyl, aralkyl or cycloalkylalkyl; and R¹¹ is hydrogen, alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heterarylalkyl.

Of this subclass of compounds, one embodiment is that set of compoundswherein n is 1; m is 1 to 3; R¹ is benzyl optionally substituted withone or more substituents selected from the group consisting of chloro,bromo, fluoro, methyl or ethyl; R² is cyano; R⁴ is hydrogen; each R⁵ isindependently selected from the group consisting of hydrogen, halo,alkyl, haloalkyl, —R⁷—OR⁸ and —R⁷—O—R⁹—OR⁸; R⁶ is a direct bond, astraight or branched ethylene chain, a straight or branched ethenylenechain or a straight or branched ethynylene chain; each R⁷ is a directbond; each R⁸ is independently selected from hydrogen, alkyl, alkenyl,haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl orcycloalkylalkyl; and each R⁹ is a straight or branched ethylene chain.

Of this subclass of compounds, another embodiment is that set ofcompounds wherein n is 1; m is 1 or 2; R¹ is benzyl optionallysubstituted with one or more substituents selected from the groupconsisting of chloro, bromo, fluoro, methyl or ethyl; R² is hydrogen,cyano, —R⁷—N(R⁸)₂, —R⁷—N(R⁸)S(O)₂R¹⁰ or —R⁷—N(R⁸)C(NR⁸)N(R⁸)₂; R³ ishaloalkyl; R⁴ is hydrogen; when m is 1, R⁵ is hydrogen or —R⁷—S(O)_(t)R⁸(where t is 0 to 2); or when m is 2, one R⁵ is —R⁷—S(O)_(t)R⁸ (where tis 0 to 2) or —R⁷—S(O)₂N(R⁸)₂ and the other R⁵ is independently selectedfrom the group consisting of alkyl, halo, haloalkyl and —R⁷—OR⁸; R⁶ is adirect bond; each R⁷ is independently a direct bond or a straight orbranched alkylene chain; each R⁸ is independently selected fromhydrogen, alkyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl,cycloalkyl or cycloalkylalkyl; and R¹⁰ is alkyl, aryl, aralkyl orcycloalkylalkyl.

Of this subclass of compounds, another embodiment is that set ofcompounds wherein n is 1; m is 1 or 2; R¹ is benzyl optionallysubstituted with one or more substituents selected from the groupconsisting of chloro, bromo, fluoro, methyl or ethyl; R² is cyano; R³ ishaloalkyl; R⁴ is hydrogen; each R⁵ is independently selected from thegroup consisting of halo, nitro, alkyl, —R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸,—R⁷—OC(O)OR⁸, —R⁷—O—R⁹—C(O)OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸ and—R⁷—N(R⁸)C(O)OR¹⁰; R⁶ is —N(H)— or a direct bond; each R⁷ isindependently a direct bond or a straight or branched alkylene chain;each R⁸ is independently selected from hydrogen, alkyl, alkenyl,haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl orcycloalkylalkyl; each R⁹ is a straight or branched alkylene chain; R¹⁰is alkyl, aryl, aralkyl or cycloalkylalkyl; and R¹¹ is hydrogen, alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heterarylalkyl.

Of the subgroup of compounds set forth above for formula (III), anotherembodiment is that class of compounds wherein Y is oxygen.

Of this class of compound, one embodiment is that subclass of compoundswherein n is 1; m is 1 to 3; R¹ is benzyl optionally substituted withone or more substituents selected from the group consisting of chloro,bromo, fluoro, methyl or ethyl; R² is cyano; R³ is haloalkyl; R⁴ ishydrogen; each R⁵ is independently selected from the group consisting ofhalo, nitro, alkyl, haloalkyl, —R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸,—R⁷—OC(O)OR⁸, —R⁷—O—R⁹—C(O)OR⁸, —R⁷—O—R⁹—OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸,—R⁷—N(R⁸)C(O)OR¹⁰ and —R⁷—S(O)_(t)R⁸ (where t is 0 to 2); R⁶ is a directbond; each R⁷ is independently selected from a direct bond or a straightor branched alkylene chain; each R⁸ is independently selected fromhydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl,aralkenyl, cycloalkyl or cycloalkylalkyl; each R⁹ is a straight orbranched alkylene chain; R¹⁰ is alkyl, aryl, aralkyl or cycloalkylalkyl;and R¹¹ is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heterarylalkyl.

Of this subclass of compounds, one embodiment is that set of compoundswherein n is 1; m is 1 to 3; R¹ is benzyl optionally substituted withone or more substituents selected from the group consisting of chloro,bromo, fluoro, methyl or ethyl; R² is cyano; R³ is trifluoromethyl; R⁴is hydrogen; each R⁵ is independently selected from the group consistingof halo, alkyl, haloalkyl, —R⁷—OR⁸ and —R⁷—O—R⁹—OR⁸; R⁶ is a directbond; each R⁷ is independently a direct bond or a straight or branchedalkylene chain; each R⁸ is independently selected from hydrogen, alkyl,alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl orcycloalkylalkyl; and each R⁹ is a straight or branched ethylene chain.

Of this subclass of compounds, another embodiment is that set ofcompounds wherein n is 1; m is 1 or 2; R¹ is benzyl optionallysubstituted with one or more substituents selected from the groupconsisting of chloro, bromo, fluoro, methyl or ethyl; R² is hydrogen,cyano, —R⁷—N(R⁸)₂, —R⁷—N(R⁸)S(O)₂R¹⁰ or —R⁷—N(R⁸)C(NR⁸)N(R⁸)₂; R³ ishaloalkyl; R⁴ is hydrogen; when m is 1, R⁵ is hydrogen or —R⁷—S(O)_(t)R⁸(where t is 0 to 2); or when m is 2, one R⁵ is —R⁷—S(O)_(t)R⁸ (where tis 0 to 2) and the other R⁵ is independently selected from the groupconsisting of halo, haloalkyl and —R⁷—OR⁸; R⁶ is a direct bond; each R⁷is a direct bond; each R⁸ is independently selected from hydrogen,alkyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl orcycloalkylalkyl; and R¹⁰ is alkyl, aryl, aralkyl or cycloalkylalkyl.

Of this subclass of compounds, another embodiment is that set ofcompounds wherein n is 1; m is 1 or 2; R¹ is benzyl optionallysubstituted with one or more substituents selected from the groupconsisting of chloro, bromo, fluoro, methyl or ethyl; R² is cyano; R³ ishaloalkyl; R⁴ is hydrogen; each R⁵ is independently selected from thegroup consisting of halo, nitro, alkyl, —R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸,—R⁷—OC(O)OR⁸, —R⁷—O—R⁹—C(O)OR⁸, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸ and—R⁷—N(R⁸)C(O)OR¹⁰; R⁶ is a direct bond; each R⁷ is independently adirect bond or a straight or branched alkylene chain; each R⁸ isindependently selected from hydrogen, alkyl, alkenyl, haloalkyl,haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl or cycloalkylalkyl;each R⁹ is a straight or branched alkylene chain; R¹⁰ is alkyl, aryl,aralkyl or cycloalkylalkyl; and R¹¹ is hydrogen, alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylor heterarylalkyl.

Another embodiment of the compounds of formula (I), as set forth abovein the Summary of the Invention, is that group of compounds having thefollowing formula (IV):

wherein n is 1 to 4; m is 1 to 4; R¹ is aralkyl; R² is cyano or—R⁷—N(R⁸)₂; R³ is haloalkyl;

is heterocyclyl or heteroaryl; each R⁴ is independently hydrogen, halo,alkyl or haloalkyl; each R⁵ is independently selected from the groupconsisting of halo, alkyl, haloalkyl, —R⁷—CN and —R⁷—C(O)OR⁸; R⁶ is —O—or a direct bond; each R⁷ is independently selected from a direct bondor a straight or branched alkylene chain; and each R⁸ is independentlyselected from hydrogen, alkyl, aryl or aralkyl; as an isomer, a mixtureof stereoisomers, a racemic mixture thereof of stereoisomers, or as atautomer; or as a pharmaceutically acceptable salt, prodrug, solvate orpolymorph thereof.

Of this group of compounds, one embodiment is that subgroup of compoundswherein R¹ is benzyl optionally substituted by one or more substituentsselected from the group consisting of chloro, bromo, fluoro, methyl orethyl;

is a N-heteroaryl selected from the group consisting of indolyl andthiazolyl; each R⁵ is independently selected from the group consistingof halo, alkyl, haloalkyl, —R⁷—CN and —R⁷—C(O)OR⁸; and R⁶ is a directbond.

Of this group of compounds, another embodiment is that subgroup ofcompounds wherein R¹ is benzyl optionally substituted by one or moresubstituents selected from the group consisting of chloro, bromo,fluoro, methyl or ethyl;

is a N-heteroaryl selected from the group consisting of indolyl,pyrimidyl, pyrazinyl, pyridinyl and thiazolyl; each R⁵ is independentlyselected from the group consisting of halo, alkyl, haloalkyl, —R⁷—CN and—R⁷—C(O)OR⁸; and R⁶ is —O—.

Of this group of compounds, another embodiment is that subgroup ofcompounds wherein R¹ is benzyl optionally substituted by one or moresubstituents selected from the group consisting of chloro, bromo,fluoro, methyl or ethyl;

is N-heterocyclyl selected from the group consisting of piperidinyl andpiperazinyl; and each R⁵ is independently selected from the groupconsisting of halo, alkyl, haloalkyl, —R⁷—CN and —R⁷—C(O)OR⁸.

Of this group of compounds, another embodiment is that subgroup ofcompounds wherein R¹ is benzyl optionally substituted by one or moresubstituents selected from the group consisting of chloro, bromo,fluoro, methyl or ethyl;

is benzodioxolyl; each R⁵ is independently selected from the groupconsisting of halo, alkyl, haloalkyl, —R⁷—CN and —R⁷—C(O)OR⁸; and R⁶ isa direct bond.

Another embodiment of the compounds of formula (I), as set forth abovein the Summary of the Invention, is that group of compounds having thefollowing formula (V):

wherein n is 1 or 2; m is 1 to 4; Y is oxygen or sulfur; R¹ is aralkyl;R² is cyano or —R⁷—N(R⁸)₂; R³ is haloalkyl; each R⁴ is independentlyhydrogen, halo, alkyl or haloalkyl;

is naphthyl, heterocyclyl or heteroaryl; each R⁵ is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, halo,haloalkyl, heterocyclyl, —R⁷—OR⁸, —R⁷—CN, —R⁷—C(O)OR⁸, —R⁷—OC(O)R¹⁰ and—R⁷—S(O)_(t)R⁸ (where t is 0 to 2); R⁶ is a direct bond; each R⁷ isindependently selected from a direct bond, a straight or branchedalkylene chain or a straight or branched alkenylene chain; each R⁸ isindependently selected from hydrogen, alkyl, alkenyl, haloalkyl,haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; R¹⁰ isalkyl, aryl, aralkyl or cycloalkylalkyl; as an isomer, a mixture ofstereoisomers, a racemic mixture thereof of stereoisomers, or as atautomer; or as a pharmaceutically acceptable salt, prodrug, solvate orpolymorph thereof.

Of this group of compounds, one embodiment is that subgroup of compoundswherein Y is —O—; R¹ is benzyl optionally substituted by one or moresubstituents selected from the group consisting of chloro, bromo,fluoro, methyl or ethyl; R³ is haloalkyl;

is a N-heteroaryl selected from the group consisting of pyrimidinyl andpyridinyl; each R⁵ is independently selected from the group consistingof hydrogen, alkyl, alkenyl, halo, haloalkyl, morpholinyl, piperazinyl,—R⁷—CN, —R⁷—OR⁸, —R⁷—C(O)OR⁸, —R⁷—OC(O)R¹⁰ and —R⁷—S(O)_(t)R⁸ (where tis 0 to 2); each R⁷ is independently a direct bond or a methylene chain;each R⁸ is hydrogen or alkyl; and R¹⁰ is alkyl or cycloalkylalkyl.

Of this group of compounds, another embodiment is that subgroup ofcompounds wherein Y is —O—; R¹ is benzyl optionally substituted by oneor more substituents selected from the group consisting of chloro,bromo, fluoro, methyl or ethyl; R³ is haloalkyl;

is heterocyclyl; each R⁵ is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, halo, haloalkyl, —R⁷—CN,—R⁷—OR⁸, —R⁷—C(O)OR⁸, —R⁷—OC(O)R¹⁰ and —R⁷—S(O)_(t)R⁸ (where t is 0 to2); each R⁷ is independently a direct bond or a methylene chain; each R⁸is hydrogen or alkyl; and R¹⁰ is alkyl or cycloalkylalkyl.

Of this group of compounds, another embodiment is that subgroup ofcompounds wherein Y is —S—; R¹ is benzyl optionally substituted by oneor more substituents selected from the group consisting of chloro,bromo, fluoro, methyl or ethyl; R³ is haloalkyl;

is a N-heteroaryl selected from the group consisting of pyridinyl,indolyl and pyrimidinyl; each R⁵ is independently selected from thegroup consisting of hydrogen, alkyl, alkenyl, halo, haloalkyl,morpholinyl, piperazinyl, —R⁷—CN, —R⁷—OR⁸, —R⁷—C(O)R⁸, —R⁷—OC(O)R¹⁰ and—R⁷—S(O)_(t)R⁸ (where t is 0 to 2); each R⁷ is independently a directbond or a methylene chain; each R⁸ is hydrogen or alkyl; and R¹⁰ isalkyl or cycloalkylalkyl.

Of this group of compounds, another embodiment is that subgroup ofcompounds wherein Y is —S—; R¹ is benzyl optionally substituted by oneor more substituents selected from the group consisting of chloro,bromo, fluoro, methyl or ethyl; R³ is haloalkyl;

is heterocyclyl; each R⁵ is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, halo, haloalkyl, —R⁷—CN,—R⁷—OR⁸, —R⁷—C(O)OR⁸, —R⁷—OC(O)R¹⁰ and —R⁷—S(O)_(t)R⁸ (where t is 0 to2); each R⁷ is independently a direct bond or a methylene chain; each R⁸is hydrogen or alkyl; and R¹⁰ is alkyl or cycloalkylalkyl.

Of this group of compounds, another embodiment is that subgroup ofcompounds wherein Y is —S—; R¹ is benzyl optionally substituted by oneor more substituents selected from the group consisting of chloro,bromo, fluoro, methyl or ethyl; R³ is haloalkyl;

is naphthyl; and each R⁵ is independently selected from hydrogen, alkyl,halo or haloalkyl.

Another embodiment of the compounds of formula (I), as set forth abovein the Summary of the Invention, is that group of compounds having thefollowing formula (VI):

wherein n is 1 or 2; m is 1 to 4; R¹ is aralkyl; R² is cyano or—R⁷—N(R⁸)₂; R³ is haloalkyl; each R⁴ is independently hydrogen, halo,alkyl or haloalkyl;

is aryl or heteroaryl; each R⁵ is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, halo, haloalkyl, —R⁷—R⁸—R⁷—CN,—R⁷—C(O)OR⁸, —R⁷—OC(O)R¹⁰ and —R⁷—S(O)_(t)R⁸ (where t is 0 to 2); R⁶ isa direct bond or a straight or branched alkylene chain; each R⁷ isindependently selected from a direct bond, a straight or branchedalkylene chain or a straight or branched alkenylene chain; each R⁸ isindependently selected from hydrogen, alkyl, alkenyl, haloalkyl,haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; and R¹⁰is alkyl, aryl, aralkyl or cycloalkylalkyl; as an isomer, a mixture ofstereoisomers, a racemic mixture thereof of stereoisomers, or as atautomer; or as a pharmaceutically acceptable salt, prodrug, solvate orpolymorph thereof.

Of this group of compounds, one embodiment is that subgroup of compoundswherein R¹ is benzyl optionally substituted by one or more substituentsselected from the group consisting of chloro, bromo, fluoro, methyl orethyl; and

is phenyl or pyridinyl; each R⁵ is independently selected from the groupconsisting of hydrogen, alkyl, halo, haloalkyl, —R⁷—OR⁸, —R⁷—CN and—R⁷—S(O)_(t)R⁸ (where t is 0 to 2); each R⁷ is a direct bond or astraight or branched alkylene chain; each R⁸ is hydrogen or alkyl; andR¹⁰ is alkyl.

Of this subgroup of compounds, one embodiment is that class of compoundswherein

is phenyl; and each R⁵ is independently selected from the groupconsisting of alkyl, halo, haloalkyl, —R⁷—OR⁸, —R⁷—CN and —R⁷—S(O)_(t)R⁸(where t is 0 to 2);

Of this subgroup of compounds, another embodiment is that class ofcompounds wherein m is 1 or 2;

is pyridinyl; and each R⁵ is independently selected from the groupconsisting of hydrogen, alkyl, halo, haloalkyl, —R⁷—OR⁸, —R⁷—CN and—R⁷—S(O)_(t)R⁸ (where t is 0 to 2).

Specific embodiments of the various groups, subgroups, classes,subclasses, set and subsets of compounds of formula (I), as set forthabove, are disclosed herein in the Examples set forth herein.

Preparation of the Compounds of the Invention

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocesses described below the functional groups of intermediatecompounds may need to be protected by suitable protecting groups. Suchfunctional groups include hydroxy, amino, mercapto and carboxylic acid.Suitable protecting groups for hydroxy include trialkylsilyl ordiarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitableprotecting groups for 1,2-dihydroxys include ketal- and acetal-forminggroups. Suitable protecting groups for amino, amidino and guanidinoinclude t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitableprotecting groups for mercapto include —C(O)—R (where R is alkyl, arylor aralkyl), p-methoxybenzyl, trityl and the like. Suitable protectinggroups for carboxylic acid include alkyl, aryl or aralkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein.

The use of protecting groups is described in detail in Green, T. W. andP. G. M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed.,Wiley-Interscience. The protecting group may also be a polymer resinsuch as a Wang resin or a 2-chlorotrityl chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of the invention, as described abovein the Summary of the Invention, may not possess pharmacologicalactivity as such, they may be administered to a mammal having a diseaseassociated with defects in cholesterol transport, glucose metabolism,fatty acid metabolism and cholesterol metabolism, and thereaftermetabolized in the body to form compounds of the invention which arepharmacologically active. Such derivatives may therefore be described as“prodrugs”. All prodrugs of compounds of the invention are includedwithin the scope of the invention.

It is understood that one of ordinary skill in the art would be able tomake the compounds of the invention not specifically prepared herein inlight of the following disclosure, including the Preparations andExamples, and information known to those of ordinary skill in thechemical synthesis field.

Starting materials in the synthesis examples provided herein are eitheravailable from commercial sources or via literature procedures or bymethods disclosed herein. All commercially available compounds were usedwithout further purification unless otherwise indicated. CDCl₃ (99.8% D,Cambridge Isotope Laboratories) was used in all experiments asindicated. ¹H NMR spectra were recorded on a Bruker Avance 400 MHz NMRspectrometer. Significant peaks are tabulated and typically include:number of protons, multiplicity (s, singlet; d, double; t, triplet; q,quartet; m, multiplet; br s, broad singlet) and coupling constant(s) inHertz. Chemical shifts are reported as parts per million (δ) relative totetramethylsilane. Mass spectra were recorded on a Perkin-Elmer SCIEXHPLC/MS instrument using reverse-phase conditions (acetonitrile/water,0.05% trifluoroacetic acid) and electrospray (ES) ionization.Abbreviations used in the examples below have their accepted meanings inthe chemical literature. For example, CH₂Cl₂ (dichloromethane), C₆H₆(benzene), TFA (trifluoroacetic acid), EtOAc (Ethyl Acetate), Et₂O(diethyl ether), DMAP (4-dimethylaminopyridine), DMF(N,N-dimethylformamide) and THF (tetrahydrofuran). Flash chromatographywas performed using Merck Silica Gel 60 (230-400 mesh).

The compounds of the invention can be prepared according to the methodsdisclosed herein or by the methods disclosed in the parent application,U.S. patent application Ser. No. 10/327,813, which is incorporatedherein by reference in its entirety, or by methods known to one skilledin the art in view of the teachings of this disclosure and theafore-mentioned parent application.

Preparation of Compounds of the Invention

For purposes of illustration only, most of the formulae in the followingReaction Schemes are directed to specific embodiments of the compoundsof invention. However, one of ordinary skill in the art, in view of theteachings of this specification and U.S. patent application Ser. No.10/327,813 would reasonably be expected to be able to prepare all thecompounds of the invention as set forth above in the Summary of theInvention utilizing the appropriately-substituted starting materials andmethods known to one skilled in the art.

In the general descriptions immediately following each Reaction Scheme,the phrase “standard isolation procedures” is meant to include one ormore of the following techniques familiar to one schooled in the art oforganic chemistry: organic extraction, washing of organic solutions withdilute aqueous acid or base, use of drying agents, filtration,concentration in vacuo, followed by purification using distillation,crystallization, or solid-liquid phase chromatography. The phrase“elevated temperature” refers to a temperature above ambient temperatureand the phrase “reduced temperature” refers to a temperature belowambient temperature.

A. Preparation of Compounds of Formula (B)

Compounds of formula (B) are starting materials in the preparation ofthe compounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 1, wherein X_(a) is bromo or iodo; m is 1 to 4; eachR^(5a) is independently hydrogen, fluoro, chloro, alkyl, haloalkyl,—OR⁸, —N(R⁸)₂ or —S(O)_(t)R⁸ (where each R⁸ is as defined in the Summaryof the Invention), and R^(10a) is alkyl, aryl or aralkyl:

1.

Compounds of formula (A) are commercially available or may be preparedaccording to methods disclosed herein or known to one skilled in the artor by methods disclosed in U.S. patent application Ser. No. 10/327,813.

In general, compounds of formula (B) are prepared by first reacting asolution of the arylhalides of formula (A) in an aprotic solvent atreduced temperature with a strong base in a metal-halogen exchangereaction to afford the organometallic reagent of formula (ZZ), whichupon reaction with a source of elemental sulfur such as S₈, provides anintermediate arylthiol (not shown). Reaction of this arylthiol with analkyl halide in the presence of a base provides the compound of formula(B) after isolation using standard procedures. In an alternate manner,the organometallic reagent of formula (ZZ) is reacted with various alkyland aryl disulfides to give compounds of formula (B) using standardisolation procedures.

B. Preparation of Compounds of Formula (Ca)

Compounds of formula (Ca) are starting materials in the preparation ofthe compounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 2, wherein X_(a) is bromo or iodo; X_(b) is bromo,chloro or iodo; m is 1 to 4; each R is hydrogen or alkyl; each R^(5a) isindependently hydrogen, fluoro, chloro, alkyl, haloalkyl or —OR⁸ (whereR⁸ is as defined in the Summary of the Invention); and R^(10a) is alkyl,aryl or aralkyl:

Compounds of formula (D) are commercially available or may be preparedaccording to methods disclosed herein or known to one skilled in the artor by methods disclosed in U.S. patent application Ser. No. 10/327,813.

In general, compounds of formula (Ca) are prepared by first exposing ananiline of formula (D) to diazotization conditions to give thearyldiazonium salt of formula (E) which, upon exposure to a source ofnucleophilic sulfur such as a xanthate salt at elevated temperature,provides the compound of formula (F) after standard isolationprocedures. Hydrolysis of the compound of formula (F) under basicconditions and exposure to an alkylating agent in the presence of a basethen provides a compound of formula (B) using standard isolationprocedures. Conversion of the compound of formula (B) to the compound offormula (Ca) is accomplished by treating the compound of formula (B) inan aprotic solvent at reduced temperature with a strong base in ametal-halogen exchange followed by reaction of the intermediateorganometallic reagent (not shown) with a trialkylborate. Alternatively,compounds of formula (B) are reacted with a diboronate or dioxaborolanereagent, such as pinacolborane in a palladium mediated couplingreaction, for example a Suzuki reaction, to give compound of formula(Ca) after standard isolation procedures.

C. Preparation of Compounds of Formula (Ka)

Compounds of formula (Ka) are starting materials in the preparation ofthe compounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 3, wherein X_(b) is bromo, chloro or iodo; m is 1 to 3;each R is hydrogen or alkyl; each R^(5b) is independently hydrogen,halo, alkyl, haloalkyl, cyano, —OR⁸, —N(R⁸)₂, —SR⁸, —C(O)OR⁸,—C(O)N(R⁸)₂; and R^(8a) is alkyl, aryl or aralkyl:

Compounds of formula (G) are commercially available or may be preparedaccording to methods disclosed herein or known to one skilled in the artor by methods disclosed in U.S. patent application Ser. No. 10/327,813.

In general, compounds of formula (Ka) are prepared by first reactinghalopyridines of formula (G) with alcohols in the presence of base andat elevated temperature to give compounds of formula (H) after standardisolation procedures. In a subsequent step, exposure of compounds offormula (H) to a brominating agent provides halopyridines of formula (J)after standard isolation procedures. Conversion of compounds of formula(J) to compounds of formula (Ka) is then accomplished by treating thecompounds of formula (J) in an aprotic solvent at reduced temperaturewith strong base in a metal-halogen exchange followed by reaction of theintermediate organometallic reagent (not shown) with a trialkylborate.Alternatively, compounds formula (J) are then reacted with a diboronateor dioxaborolane reagent such as pinacolborane in a palladium mediatedcoupling reaction, for example a Suzuki reaction, to give compounds offormula (Ka) after standard isolation procedures.

D. Preparation of Compounds of Formula (Kb)

Compounds of formula (Kb) are intermediates in the preparation of thecompounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 4, wherein each X_(b) is bromo, chloro or iodo; m is 1to 3; each R is hydrogen or alkyl; each R^(5b) is independentlyhydrogen, halo, alkyl, haloalkyl, cyano, —OR⁸, —N(R⁸)₂, —SR⁸, —C(O)OR⁸,—C(O)N(R⁸)₂; and R^(10a) is alkyl, aryl or aralkyl:

Compounds of formula (L) are commercially available or may be preparedaccording to methods disclosed herein or known to one skilled in the artor by methods disclosed in U.S. patent application Ser. No. 10/327,813.

In general, compounds of formula (Kb) are prepared by first reactingdihalopyridines of formula (L) with thiols in the presence of base andat elevated temperature to give sulfides of formula (M) after standardisolation procedures. Conversion of compounds of formula (M) tocompounds of formula (Kb) is then accomplished by treating compounds offormula (M) in an aprotic solvent at reduced temperature with strongbase in a metal-halogen exchange followed by reaction of theintermediate organometallic reagent with a trialkylborate.Alternatively, compounds (M) are reacted with a diboronate ordioxaborolane reagent such as pinacolborane in a palladium mediatedcoupling reaction, for example a Suzuki reaction, to give compounds offormula (Kb) after standard isolation procedures.

E. Preparation of Compounds of Formula (Cb)

Compounds of formula (Cb) are starting materials in the preparation ofthe compounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 5, wherein X_(a) is bromo or iodo; X_(b) is bromo,chloro or iodo; each m is 1 to 4; each R is hydrogen or alkyl; eachR^(5c) is independently hydrogen, fluoro, chloro, alkyl, haloalkyl,—OR⁸, —N(R⁸)₂; and R^(8a) is alkyl, aryl or aralkyl:

Compounds of formula (A) are commercially available or may be preparedaccording to methods disclosed herein or known to one skilled in the artor by methods disclosed in U.S. patent application Ser. No. 10/327,813.

In general, compounds of formula (Cb) are prepared by first reactingaryldihalides of formula (A) with strong base in an aprotic solvent atreduced temperature in a metal-halogen exchange reaction followed bycarbonylation of the intermediate organometallic reagent (not shown) togive the carboxylic acids of formula (N) after standard isolationprocedures. Conversion of compounds of formula (N) to compounds offormula (P) is then accomplished using the Arndt-Eistert reactionsequence, namely, preparation of the acylchloride (not shown) usingstandard methods, generation of the intermediate diazoketone (not shown)by treatment of the acylchloride with diazomethane at reducedtemperature, followed by exposure of the diazoketone to a silver-salt ofan organic acid in the presence of an alcohol and isolation usingstandard procedures. Palladium mediated coupling of compounds of formula(P) with a diboronate or dioxaborolane reagent such as pinacolboraneprovides arylboronates of formula (Cb) after standard isolationprocedures.

F. Preparation of Compounds of Formula (Pb)

Compounds of formula (Pb) are starting materials in the preparation ofthe compounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 6, wherein X_(a) is bromo or iodo; X_(b) is bromo,chloro or iodo; m is 1 to 4; each R is alkyl or aralkyl; each R^(5c) isindependently hydrogen, fluoro, chloro, alkyl, haloalkyl, —OR⁸ or—N(R⁸)₂; R^(7a) is alkyl, aralkyl or fluoro, and R^(8a) is alkyl, arylor aralkyl:

Compounds of formula (P) are commercially available or may be preparedaccording to methods disclosed herein or known to one skilled in the artor by methods disclosed in U.S. patent application Ser. No. 10/327,813.

In general, compounds of formula (Pb) are prepared by first treatingcompounds of formula (P) with a strong base in an aprotic solvent atreduced temperature followed by the addition of an alkylating orfluorinating agent to give compounds of formula (Pa). Reaction ofcompounds of formula (Pa) with additional base and subsequent treatmentwith a second portion of alkylating or fluorinating agent providescompounds of formula (Pb) after standard isolation procedures.

G. Alternate Preparation of Compounds of Formula (Cb)

Compounds of formula (Cb) are starting materials in the preparation ofthe compounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 7, wherein each m is 1 to 4; each R is hydrogen oralkyl; each R^(5d) is independently hydrogen, chloro, fluoro, alkyl,haloalkyl; and R^(8a) is alkyl, aryl or aralkyl:

Compounds of formula (Q) are commercially available or may be preparedaccording to methods disclosed herein or known to one skilled in the artor by methods disclosed in U.S. patent application Ser. No. 10/327,813.

In general, compounds of formula (Cb) are prepared by first reactingsubstituted methylbenzenes of formula (Q) under free radical conditionsin the presence of a halogenating agent to give benzyl halides offormula (R) which, upon exposure to a cyanide source, afford benzylcyanides of formula (S) after standard isolation procedures. Treatmentof an alcoholic solution of benzyl cyanides of formula (S) in thepresence of strong acid provides esters of formula (P) after standardisolation procedures. Palladium mediated coupling of compounds offormula (P) with a diboronate or dioxaborolane reagent such aspinacolborane provides arylboronates of formula (Cb) after standardisolation procedures.

Alternatively, compounds of formula (Cb) are prepared by reactingcompounds of formula (Pa) or compounds of formula (Pb), as describedabove in Reaction Scheme 6, under similar conditions as described abovein Step 3 of Reaction Scheme 7 to produce compounds of formula (Cb)wherein the —CH₂—C(O)OR^(8a) substituent is either—C(R^(7a))H—C(O)OR^(8a) or —C(R^(7a))₂—C(O)OR^(8a), respectively.

H. Preparation of Compounds of Formula (Ta)

Compounds of formula (Ta) are starting materials in the preparation ofthe compounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 8, wherein R is alkyl:

Compounds of formula (AA) are commercially available or may be preparedaccording to methods disclosed herein or known to one skilled in the artor by methods disclosed in U.S. patent application Ser. No. 10/327,813.

In general, compounds of formula (Ta) are prepared by first reacting thearylhalide of formula (AA) with 2-methyl-3-butyn-2-ol in the presence ofpalladium and a copper(I) salt to give the alkyne of formula (BB) afterstandard isolation procedures. Exposure of alkyne of formula (BB) tostrong base at elevated temperature affords the alkyne of formula (CC)which is then, under standard conditions of catalytic hydrogenation,converted to the nitrile of formula (DD) after standard isolationprocedures. Reduction of the nitrile of formula (DD) with a metalhydridereagent provides the benzylamine of formula (EE) after standardisolation procedures. Conversion of the benzylamine of formula (EE) tothe compound of formula (Ta) is then accomplished by either treating asolution of the benzylamine of formula (EE) with the acylchlorideprepared from cyanoacetic acid under standard conditions, in thepresence of a base, or by heating a solution of the benzylamine offormula (EE) with a cyanoacetic ester in the presence of a base such asN,N-dimethylaminopyridine (DMAP) to give the compounds of formula (Ta)after standard isolation procedures.

I. Preparation of Compounds of Formula (Ua)

Compounds of formula (Ua) are starting materials in the preparation ofthe compounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 9, wherein n is 1 to 4; each R is alkyl or aralkyl;R^(3a) is alkyl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl,cycloalkylalkyl, heterocyclyl or heterocyclylalkyl; each R^(4a) ishydrogen, fluoro, chloro, alkyl or haloalkyl; and

is aryl or heteroaryl:

Compounds of formula (FF) and (GG) are commercially available or may beprepared according to methods disclosed herein or known to one skilledin the art or by methods disclosed in U.S. patent application Ser. No.10/327,813.

In general, compounds of formula (Ua) are prepared by first treating theoxalate diesters of formula (FF) with an organometallic reagent, such asa Grignard reagent, in an aprotic solvent at reduced temperature to givethe α-ketoesters of formula (GG) after standard isolation procedures.Treatment of the ketoesters of formula (GG) with a fluorinating agent,such as (diethylamino)sulfur trifluoride (DAST), affords the2,2-difluoroesters of formula (HH) after standard isolation procedures.Reaction of 2,2-difluoroesters of formula (HH) with methylketones offormula (W) under Claisen condensation conditions provides the diketonesof formula (Ua) after standard isolation procedures.

J. Preparation of Compounds of Formula (I)

Compounds of formula (Ia) are compounds of formula (I) wherein R⁶ is adirect bond and are prepared according to methods known to one skilledin the art or by the method described below in Reaction Scheme 10,wherein n, m, R¹, R², R³, R⁴ and R⁵ are as defined above in the Summaryof the Invention, and

is aryl or heteroaryl and

is aryl or heteroaryl:

Compounds of formula (T) and (U) are commercially available or may beprepared according to methods disclosed herein or known to one skilledin the art or by methods disclosed in U.S. patent application Ser. No.10/327,813.

In general, compounds of formula (Ia), which are compounds of formula(I), are prepared by first combining cyanoacetamides of formula (T) withdiketones of formula (U) in the presence of base and at elevatedtemperature to give 2-pyridones of formula (V) after standard isolationprocedures. Treatment of the pyridones of formula (V) with boronates offormula (C) under palladium-catalyzed coupling conditions (Suzukireaction) provides the compounds of formula (Ia) after standardisolation procedures. Compounds of formula (Ia) can be further convertedto various derivatives using general methods of organic chemistry knownto those skilled in the art and/or by methods disclosed herein.

K. Preparation of Compounds of Formula (Ib)

Compounds of formula (Ib) are compounds of formula (I) wherein R⁶ is adirect bond and are prepared according to methods known to one skilledin the art or by the method described below in Reaction Scheme 11,wherein R is hydrogen or alkyl, X_(b) is bromo, chloro or iodo, and n,m, R¹, R², R³, R⁴ and R⁵ are as defined above in the Summary of theInvention, and

is aryl or heteroaryl and

is aryl or heteroaryl:

Compounds of formula (W) and (Ga) are commercially available or may beprepared according to methods disclosed herein or known to one skilledin the art or by methods disclosed in U.S. patent application Ser. No.10/327,813.

In general, compounds of formula (Ib) are prepared by first, which arecompounds of formula (I), are prepared by first treating compounds offormula (W) with a diboronate or dioxaborolane reagent such aspinacolborane under palladium mediated coupling conditions to give theboronates of formula (X) after standard isolation procedures. In asecond palladium catalyzed coupling (Suzuki reaction), boronates offormula (X) are combined with halides of formula (Ga) to givemethylketones of formula (Y) after standard isolation procedures. Thereaction of esters of formula (NN) with methylketones of formula (Y) inthe presence of strong base, for example, under Claisen condensationconditions, provides the diketones of formula (Z) after standardisolation procedures. The diketones of formula (Z) undergo acondensation reaction with amides of formula (T) in the presence of baseand at elevated temperature to give the 2-pyridones of formula (Ib)after standard isolation procedures. Compounds of formula (Ib) can befurther converted to various derivatives using general methods oforganic chemistry known to those skilled in the art and/or by methodsdisclosed herein.

L. Preparation of Compounds of Formula (Ya)

Compounds of formula (Ya) are starting materials in the preparation ofthe compounds of the invention and can be prepared according to methodsknown to one skilled in the art or by the method described below inReaction Scheme 12, wherein each X is halo; X_(a) is bromo or iodo; n is1 or 2; R^(4c) is hydrogen, fluoro, chloro, alkyl or haloalkyl; m, R¹,R², R³, R⁴ and R⁵ are as defined above in the Summary of the Invention,and

is aryl or heteroaryl:

Compounds of formula (JJ), (Gc) and (LL) are commercially available ormay be prepared according to methods disclosed herein or known to oneskilled in the art or by methods disclosed in U.S. patent applicationSer. No. 10/327,813.

In general, compounds of formula (Ya) are prepared by first reactinghalopyrazoles of formula (JJ) with halides of formula (Gc) in thepresence of base at elevated temperatures to give the pyrazolederivatives of formula (KK) after standard isolation procedures.Treatment of the pyrazole derivatives of formula (KK) with strong basein an aprotic solvent at reduced temperature under conditions ofmetal-halogen exchange gives the intermediate organometallic reagent(not shown), followed by the addition of an acylating agent effective atreduced temperatures, such as the compound of formula (LL), provides thepyrazolemethylketones of formula (Ya) after standard isolationprocedures.

The following specific Preparations (for intermediates) and Examples(for compounds, pharmaceutical compositions and methods of use of theinvention) are provided as a guide to assist in the practice of theinvention, and are not intended as a limitation on the scope of theinvention.

Preparation 1 Compounds of Formula (B)

1,3-Dibromo-5-ethyl-benzene (1.54 g, 5.8 mmoles) was dissolved intoanhydrous THF (20 mL) under nitrogen, and was chilled to −78° C. To thisstirring solution was slowly (over 10 min) added t-BuLi (3.8 mL, 6.5mmoles, 1.7M solution in pentane). After the addition was complete themixture was allowed to stir at −78° C. for an additional 30 min. Afterthis period isopropyl disulfide (1.4 mL, 8.8 mmoles) was added and themixture was allowed to warm to ambient temperature. The reaction wasthen warmed to 75° C., and was stirred at this temperature for 16 hours.After this period the reaction mix was evaporated in vacuo and waspurified using flash silica chromatography (0-1% EtOAc/Hexane) to yield1-bromo-3-ethyl-5-isopropylsulfanyl-benzene (1.08 g, 72%) as a clearliquid. ¹H-NMR (CDCl₃): δ 7.34-7.32 (m, 1H), 7.19-7.17 (m, 1H),7.13-7.11 (m, 1H), 3.39 (m, J=6.6 Hz, 1H), 2.59 (q, J=7.6 Hz, 2H), 1.30(d, J=6.6 hz, 6H), 1.22 (t, J=7.6 Hz, 3H).

Preparation 2 Compounds of Formula (F)

3-Bromo-5-trifluoromethyl-phenylamine (4.0 mL, 28.3 mmoles) wasdissolved into concentrated HCl (70 mL). This solution was chilled to 0°C. and to it was slowly added a solution of sodium nitrite (2.5 g, 36.2mmoles) in 50 mL of water. After completion of the addition enoughethanol (90%) was added (25 mL) to affect nearly complete dissolution ofthe resultant mixture. The mixture was stirred at 0° C. for anadditional 20 minutes. After this period the heterogeneous mixture wasquickly transferred (cold) to an addition funnel. The diazonium mixturewas added to a solution of O-ethylxanthic acid, potassium salt (5.7 g,35.6 mmoles) in 50 mL of water at 60° C. The mixture was next heated to90° C. and was stirred at this temperature for 2 hours. After thisperiod the mixture was allowed to cool to ambient temperature, and thecrude xanthate (a red liquid) was removed from the bottom of the aqueousmixture via pipette. The crude product taken up in 100 mL of diethylether and was washed with water (2×25 mL) and brine (20 mL). The etherlayer was evaporated in vacuo to yield crude xanthate. The crude productwas purified using flash silica chromatography (0-1% EtOAc/Hexane) toyield 4.7 g (51% yield) of dithiocarbonic acidS-(3-bromo-5-trifluoromethyl-phenyl) ester O-ethyl ester as a redliquid. ¹H-NMR (CDCl₃): δ 7.83 (d, J=5.8 Hz, 2H), 7.71 (s, 1H), 4.63 (q,J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).

Preparation 3 Compounds of Formula (B)

Dithiocarbonic acid S-(3-bromo-5-trifluoromethyl-phenyl) ester O-ethylester (3.3 g, 10.3 mmoles) was dissolved into 30 mL of EtOH, 10 mL ofH₂O, and was sealed under nitrogen. To this stirring mixture was addedKOH (2.8 g, 50 mmoles) and this mix was stirred at reflux (undernitrogen) for 12 hours. After this period the reaction mixture wasevaporated in vacuo and combined with 50 mL of water. The pH wasadjusted to <2 using 6N HCl and the resulting mixture was extracted withdiethyl ether (3×50 mL). The combined ethereal layer was washed withbrine and dried over anhydrous MgSO₄. Following evaporation in vacuo thecrude thiol was dissolved into 50 mL of acetone. Ethyl bromide (1.5 mL,20.1 mmoles) and K₂CO₃ (5 g, 36.2 mmoles) were added, and the mixturewas stirring at ambient temperature (under nitrogen) for 6 hours. Afterthis period the mixture was gravity filtered, and evaporated in vacuo toyield crude product. The crude product was purified using flash silicachromatography (0-1% EtOAc/Hexane) to yield1-bromo-3-ethylsulfanyl-5-trifluoromethyl-benzene (1.33 g, 45% yield) asa yellowish liquid. ¹H-NMR (CDCl₃): δ 7.56 (s, 1H), 7.52 (s, 1H), 7.43(s, 1H), 3.0 (q, J=7.3 Hz, 2H), 1.36 (t, J=7.3 Hz, 3H).

Preparation 4 Compounds of Formula (Ca)

1-Bromo-3-ethylsulfanyl-5-trifluoromethyl-benzene (1.33 g, 4.7 mmoles)was placed into a 50 mL pear-shaped flask and was sealed under nitrogen.The material was then solubilized with 25 mL of anhydrous DMSO, and theresulting solution was degassed by passing a steady stream of nitrogenthrough the solution for 10 min. In a separate round-bottom flask werecombined bis(pinacolato)diboron (1.3 g, 5.1 mmoles),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith DCM (1:1) (0.11 g, 0.13 mmoles) and potassium acetate (1.4 g, 14.3mmoles) with a stirring bar under nitrogen. Following degassificationthe bromide solution was transferred to the “catalytic” mixture and theresulting mix was stirred at 90° C. for 16 hours. After this period thereaction mix was combined with 100 mL of water and was extracted withbenzene (4×30 mL). The combined benzene layer was washed with water(4×50 mL) and was dried over anhydrous Na₂SO₄. Following evaporation invacuo the crude product was purified using flash silica chromatography(0-1% EtOAc/Hexane) to yield2-(3-ethylsulfanyl-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(651 mg, 41% yield) was a thick, clear liquid. Note: TLC visualizationaccomplished using ceric ammonium molybdate stain. ¹H-NMR (CDCl₃): δ7.89 (s, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 3.01 (q, J=7.3 Hz, 2H), 1.35(s, 12H), 1.33 (t, J=7.3 Hz, 3H).

Preparation 5 Compounds of Formula (H)

2-Chloro-3-trifluoromethyl-pyridine (4.43 g, 24.4 mmol) was dissolved in42 ml 21% (wt.) sodium ethoxide in ethanol. The mixture was stirred atambient temperature for 1.5 days. After this period of time, the solventwas evaporated and the residue was taken into water and extracted withdichloromethane three times. The combined extract was washed with brine,dried over sodium sulfate, and concentrated in vacuo to give2-ethoxy-3-trifluoromethyl-pyridine as a light liquid (3.42 g, 73%yield). The crude product was used directly for the next step. ¹H-NMR(400 MHz, CDCl₃): δ 1.42 (t, 3H, J=7.07), 4.49 (q, 2H, J=7.07), 6.94(dd, 1H, J=7.45, J=5.05), 7.85 (dd, 1H, J=1.26, J=7.45), 8.30 (dd, 1H,J=1.26, J=5.06).

Preparation 6 Compounds of Formula (J)

2-Ethoxy-3-trifluoromethyl-pyridine (900 mg, 4.71 mmol) and1,3-dibromo-5,5-dimethylhydantoin (1.35 g, 4.71 mmol) were placed in around-bottom flask. To this mixture was slowly added 10 mLtrifluoroacetic acid. The mixture was stirred at ambient temperature forovernight. More 1,3-dibromo-5,5-dimethylhydantoin (540 mg, 1.9 mmol) wasadded and the reaction mixture was stirred at ambient temperature foranother day. After the completion of the reaction, TFA solvent wasevaporated in vacuo and the resulting residue was neutralized to pH 7 bythe addition of saturated NaHCO₃. The aqueous layer was extracted withdichloromethane three times and the combined extract was washed withbrine, dried over sodium sulfate, and concentrated in vacuo to give amixture of oil and white solid. The residue was redissolved into 20%EtOAc/Hexane, and the unsoluable white solid was filtered out. Thefiltrate was concentrated and then purified by column chromatography onsilica gel (10% EtOAC/Hexane) to give5-bromo-2-ethoxy-3-trifluoromethyl-pyridine as a colorless liquid (1.0g, 79% yield). ¹H-NMR (400 MHz, CDCl₃): δ 1.41 (t, 3H, J=7.07), 4.46 (q,2H, J=7.07), 7.94 (dd, 1H, J=0.51, J=2.53), 8.34 (dd, 1H, J=0.51,J=2.53).

Preparation 7 Compounds of Formula (Ka)

A. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1), (286 mg, 0.35 mmol), potassium acetate (1.55g, 15.8 mmol), and bis(pinacolato)diboron (1.3 g, 5.3 mmol) were placedinto a vial and degassed with stream of nitrogen for 20 min. In aseparate vial, 5-bromo-2-ethoxy-3-trifluoromethyl-pyridine (945 mg, 3.5mmol) was dissolved in 7 ml anhydrous DMSO and degassed with stream ofnitrogen for 20 min. The DMSO solution of5-bromo-2-ethoxy-3-trifluoromethyl-pyridine was added to the “catalyst”vial, and then heated at 80° C. overnight. After cooling to ambienttemperature, water and ethyl acetate were added to the reaction mixtureand the aqueous layer was extracted with ethyl acetate. The combinedextract was washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (10→30% EtOAC/Hexane) to give2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridineas solid (1.08 g, 97% yield). ¹H-NMR (400 MHz, CDCl₃): δ 1.35 (s, 12H),1.42 (t, 3H, J=7.07), 4.52 (q, 2H, J=7.07), 8.20 (d, 1H, J=1.01), 8.64(d, 1H, J=1.26).

B. Alternatively, n-butyl lithium (1.6 M solution in hexane, 0.9 mL,1.43 mmol) was slowly added to a solution of5-bromo-2-ethoxy-3-trifluoromethyl-pyridine (352 mg, 1.3 mmol) in 2.6 mLanhydrous Et₂O at −78° C. under nitrogen. The mixture was kept at −78°C. for 1 hr, and then to this mixture was added triisopropyl borate (489mg, 2.6 mmol). The mixture was allowed to warm to ambient temperatureovernight. The reaction was quenched by water and the pH was adjusted to5 by carefully addition of 1N aqueous HCl. Two layers were separated andthe aqueous layer was extracted with ethyl acetate three times. Theextract was washed with brine, dried over sodium sulfate, andconcentrated in vacuo to give2-ethoxy-3-trifluoromethylpyridine-5-boronic acid as a brown oil (240mg, 67% yield). The product was used for the next step withoutpurification.

Preparation 8 Compounds of Formula (M)

A. 2,5-Dibromo-pyridine (3.0 g, 12.7 mmol) and sodium thiomethoxide(0.84 g, 12 mmol) were dissolved in 18 ml anhydrousN,N-dimethylformamide. The mixture was heated at 160° C. under nitrogenfor 6 hrs. After cooling to ambient temperature, water and ethyl acetatewere added to the reaction mixture. The aqueous layer was extracted withethyl acetate several times. The combined extract was washed with brine,dried over sodium sulfate, and concentrated in vacuo. The crude productwas purified by column chromatography on silica gel (0→6% EtOAC/Hexane)to give 5-bromo-2-methylsulfanyl-pyridine as a white solid (2.18 g, 84%yield). ¹H-NMR (400 MHz, CDCl₃): δ 2.55 (s, 3H), 7.09 (dd, 1H, J=0.7,J=8.6), 7.59 (dd, 1H, J=2.4, J=8.6), 8.50 (m, 1H).

B. Alternatively, 2-bromo-5-nitro-pyridine (1.22 g, 6.0 mmoles),TMS-acetylene (0.9 mL, 6.4 mmoles), CuI (11 mg, 0.06 mmoles) anddichlorobis(triphenylphosphine)palladium (II) (210 mg, 0.3 mmoles) werecombined and flushed with dry nitrogen for 10 min. After this period themix was solubilized with 24 mL of anhydrous triethylamine (degassed),and the mix was stirred at ambient temperature for 4 hours. After thisperiod the reaction mix was evaporated in vacuo and purified directlyusing flash silica chromatography (0-10% EtOAc/Hexane) to yield5-nitro-2-trimethylsilanylethynyl-pyridine as a brown solid. Thismaterial was dissolved into THF (10 mL) and to this solution was added100 mg of TFAB (on silica gel, 1.0-1.5 mmole F/g resin). The solutionwas stirred at ambient temperature for 15 min. After this period thereaction mix was evaporated in vacuo purified directly using flashsilica chromatography (0-20% EtOAc/Hexane) to yield2-ethynyl-5-nitro-pyridine as a clear liquid. This product was combinedwith 10% Pd/C (90 mg) and ethanol (20 ml) and was flushed with drynitrogen. After oxygen exclusion the stirring mix was flushed with H₂and stirred under H₂ pressure (balloon) for 16 hours. After this periodthe reaction mixture was flushed with nitrogen and then filtered throughCelite. The filtrate was evaporated in vacuo and purified using flashsilica chromatography (0-10% MeOH/DCM w/0.1% diethylamine) to yield6-ethyl-pyridin-3-ylamine (442 mg, 60%-3 steps) as a brownish residue.¹H-NMR (CDCl₃): δ 8.05-8.02 (m, 1H), 6.96-6.93 (m, 2H), 3.55 (br s, 2H),2.71 (q, J=7.3 Hz, 2H), 1.25 (t, J=7.3 Hz, 3H).

C. 6-Ethyl-pyridin-3-ylamine (442 mg, 3.62 mmoles) was dissolved into 30mL of MeOH and 3 mL of HOAc and the resulting solution was chilled to 0°C. To this stirring mixture was slowly added a solution of bromine (0.41mL, 8.0 mmoles) in 5 mL of HOAc. The mix was then allowed to warm toambient temperature and was stirred at this temperature for 16 hours.After this period the reaction mix was evaporated in vacuo, combinedwith saturated NaHCO₃ (15 mL), and extracted with DCM (3×20 mL). The DCMlayer was dried over anhydrous Na₂SO₄ and was evaporated in vacuo toyield the crude product was a brownish solid. The crude product waspurified using flash silica chromatography (0-10% EtOAc/Hexane) to yield2,4-dibromo-6-ethyl-pyridin-3-ylamine (868 mg, 86%) as a brown solid.¹H-NMR (CDCl₃): δ 252-827.18 (s, 1H), 4.41 (br s, 2H), 2.68 (q, J=7.6Hz, 2H), 1.24 (t, J=7.6 Hz, 3H).

D. 2,4-Dibromo-6-ethyl-pyridin-3-ylamine (105 mg, 0.38 mmoles) wascombined with 80% sodium thioethoxide (50 mg, 0.48 mmoles) in anhydrousDMF (2 mL) and was stirred at 50° C. under nitrogen for 2 hours. Afterthis period the reaction mix was combined with water (20 mL) and wasextracted with EtOAc (3×20 mL). The combined EtOAc layer was washed withwater (3×15 mL) and brine. After drying over anhydrous Na₂SO₄ theorganic layer was evaporated in vacuo to yield crude product. The crudeproduct was purified using flash silica chromatography (0-15%EtOAc/Hexane) to yield 4-bromo-6-ethyl-2-ethylsulfanyl-pyridin-3-ylamine(83 mg, 84%) as a clear residue. ¹H-NMR (CDCl₃): δ 6.94 (s, 1H), 4.34(br s, 2H), 2.95 (q, J=7.3 Hz, 2H), 2.68 (q, J=7.6 Hz, 2H), 1.33 (t,J=7.3 Hz, 3H), 1.24 (t, J=7.6 Hz, 3H).

E. 4-Bromo-6-ethyl-2-ethylsulfanyl-pyridin-3-ylamine (476 mg, 1.82mmoles) was dissolved into EtOH (5 mL) and chilled to −10° C. undernitrogen. At −10° C. 48% wt. aq. HBF₄ (1.0 mL) was added and thetemperature was further lowered to −25° C. At −25° C. isoamyl nitrite(0.256 mL, 1.9 mmoles) was slowly added (over 1 min), and thetemperature was allowed to warm to −5° C. The reaction was stirred at−5° C. for 30 min. After this period the reaction mix was chilled to−25° C. and an excess of 50% aqueous H₃PO₂ (5.0 mL) was added. The mixwas then allowed to warm to ambient temperature and was stirred at thistemperature for 1 hour (vigorous bubbling is observed). After thisperiod the reaction was combined with 40 mL of diethyl ether followed(carefully) by saturated NaHCO₃ (10 mL). The mix was then extracted withdiethyl ether (2×20 mL) and the resultant ether layer was washed withbrine. After drying over anhydrous MgSO₄ the ethereal layer wasevaporated in vacuo to yield crude product. The crude product waspurified using flash silica chromatography (0-10% EtOAc/Hexane) to yield4-bromo-2-ethylsulfanyl-6-ethylpyridine (340 mg, 76%) as a golden-yellowliquid. ¹H-NMR (CDCl₃): δ 7.09 (br d, J=1.3 Hz, 1H), 6.90 (br d, J=1.5Hz, 1H), 3.0 (q, J=7.3 Hz, 2H), 2.73 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.3Hz, 3H), 1.27 (t, J=7.6 Hz, 3H).

Preparation 9 Compounds of Formula (Kb)

Palladium catalyst([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1), 167 mg, 0.21 mmol), potassium acetate (1.81g, 18.5 mmol, Aldrich), and bis(pinacolato)diboron (1.56 g, 6.1 mmol)were placed into a vial and degassed with stream of nitrogen for 20 min.In a separate vial, 5-bromo-2-methylsulfanylpyridine (836 mg, 4.1 mmol)was dissolved in 8 ml anhydrous DMSO and degassed with stream ofnitrogen for 20 min. The DMSO solution of5-bromo-2-methylsulfanylpyridine was added to the “catalyst” vial, andthen heated at 80° C. overnight. After cooling to ambient temperature,water and ethyl acetate were added to the reaction mixture. The aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over sodium sulfate, and concentrated in vacuo.The crude product was purified by column chromatography on silica gel(10→30% EtOAC/Hexane, 0.25% Et₃N in hexane) to give2-methylsulfanyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridineas a colorless oil (1.00 g, 97% yield). ¹H-NMR (400 MHz, CDCl₃): δ 1.35(s, 12H), 2.58 (s, 3H), 7.16 (dd, 1H, J=1.0, J=8.0), 7.83 (dd, 1H,J=1.8, J=8.0), 8.50 (dd, 1H, J=1.7, J=1.0)

Preparation 10 Compounds of Formula (N)

1,3-Dibromo-5-isopropyl-benzene (1.57 g, 5.65 mmoles) was dissolved intoanhydrous THF (50 mL) under nitrogen, and was chilled to −78° C. To thisstirring solution was slowly (over 10 min) added t-BuLi (3.6 mL, 6.1mmoles, 1.7M solution in pentane). After the addition was complete themixture was allowed to stir at −78° C. for an additional 30 min. Afterthis period CO₂ was bubbled through the stirring solution and thetemperature was allowed to warm to ambient temperature. CO₂ bubbling wascontinued for 3 hours and afterwards the reaction was allowed to stirfor an additional 6 hours. After this period 1H HCl (10 mL) was addedand the mix was evaporated in vacuo (-THF). The resulting aqueousmixture was extracted with DCM (3×20 mL) and the organic layer was driedover anhydrous Na₂SO₄. Evaporation in vacuo yielded the crude carboxylicacid as a white solid. The crude acid (1.22 g, ˜5.0 mmoles) wasdissolved into C₆H₆ (20 mL) and to this was added freshly distilledthionyl chloride (0.5 mL, 6.9 mmoles). This mixture was heated to refluxand stirred at this temperature for 16 hours. After this period thereaction mix was evaporated in vacuo to yield crude3-bromo-5-isopropyl-benzoyl chloride (1.0 g, 68%—2 steps) as a yellowliquid. ¹H-NMR (CDCl₃): δ 8.08 (t, J=1.8 Hz, 1H), 7.89-7.87 (m, 1H),7.68-7.66 (m, 1H), 2.98 (m, J=6.8 Hz, 1H), 1.28 (d, J=6.8 Hz, 6H).

Preparation 11 Compounds of Formula (P)

A. Potassium Hydroxide (1 g) was added to an erlenmeyer flask containingwater (40 mL) and diethyl ether (50 mL) at 0° C. The mixture was stirredto fully solubilize the hydroxide. 1-Methyl-3-nitro-1-nitrosoguanidine(2.24 g, 15.2 mmoles) was added to this flask in aliquots to generate asolution of diazomethane in ether. A separate erlenmeyer flask waschilled to −78° C. Ether from the diazomethane “generator” wastransferred via pipette to this “cold” flask. When nearly all of theether (diazomethane) had been transferred to the “cold” flask, asolution of 3-Bromo-5-isopropyl-benzoyl chloride (796 mg, 3.0 mmoles) in10 mL of diethyl ether was added to the “cold” flask. The “cold” flaskwas then allowed to warm to 0° C. and was stirred at this temperaturefor 2 hrs. After this period the reaction mixture was thoroughly purgedusing nitrogen gas (bubbling). The resulting ether solution wasevaporated in vacuo and the crude product was purified using flashsilica chromatography (0-10% EtOAc/Hexane) to yield the intermediatediazoketone (696 mg, 86%) as a yellow solid. ¹H-NMR (CDCl₃): δ 7.66 (brt, J=1.8 Hz, 1H), 7.57-7.55 (m, 1H), 7.54-7.52 (m, 1H), 5.86 (s, 1H),2.94 (m, J=6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H).

B. The diazoketone (696 mg, 2.61 mmoles) was dissolved into MeOH (20 mL)and to this solution at ambient temperature was added a solution ofAgOBz (340 mg, 1.49 mmoles) in NEt₃ (4.2 mL). This mixture was stirredat ambient temperature for 30 min. After this period the reaction mixwas filtered through Celite and evaporated in vacuo to yield crudeproduct. The crude product was purified using flash silicachromatography (0-10% EtOAc/Hexane) to yield(3-bromo-5-isopropyl-phenyl)-acetic acid methyl ester (0.514 g, 62%—2steps) as a yellow residue. ¹H-NMR (CDCl₃): δ 7.28-7.25 (m, 2H),7.06-7.04 (m, 1H), 3.71 (s, 3H), 3.57 (s, 2H), 2.86 (m, J=6.8 Hz, 1H),1.23 (d, J=6.8 Hz, 6H).

Preparation 12 Compounds of Formula (Cb)

A. (3-Bromo-5-isopropyl-phenyl)-acetic acid methyl ester (0.514 g, 1.9mmoles) was place into a 25 mL pear-shaped flask and was sealed undernitrogen. The material was then solubilized with 13 mL of anhydrousDMSO, and the resulting solution was degassed by passing a steady streamof nitrogen through the solution for 10 min. In a separate round-bottomflask were combined bis(pinacolato)diboron (0.58 g, 2.3 mmoles),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith DCM (1:1) (50 mg, 0.061 mmoles) and potassium acetate (0.56 g, 5.7mmoles) with a stirring bar under nitrogen. Following degassificationthe bromide solution was transferred to the “catalytic” mixture and theresulting mix was stirred at 90° C. for 16 hours. After this period thereaction mix was combined with 60 mL of water and was extracted withbenzene (4×15 mL). The combined benzene layer was washed with water(4×25 mL) and was dried over anhydrous Na₂SO₄. Following evaporation invacuo the crude product was purified using flash silica chromatography(0-10% EtOAc/Hexane) to yield[3-isopropyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-aceticacid methyl ester (502 mg, 83% yield) was a thick, greenish liquid. TLCvisualization accomplished using ceric ammonium molybdate stain. ¹H-NMR(CDCl₃): δ 269-167.58 (br s, 1H), 7.53 (br s, 1H), 7.26-7.23 (m, 1H),3.68 (s, 3H), 3.62 (s, 2H), 2.91 (m, J=6.8 Hz, 1H), 1.34 (s, 12H), 1.25(d, J=6.8 Hz, 6H).

B. Alternatively, a suspension of 2-(3-bromo-phenyl)-2-methyl-propionicacid methyl ester (755 mg, 2.9 mmol), and potassium acetate (880 mg, 8.9mmol) was prepared in DMSO (15 mL). Nitrogen was bubbled through thesuspension to deoxygenate the mixture. Bis(pinacolato)diboron (980 mg,3.8 mmol) was added to the suspension, followed bydichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium (II)dichloromethane adduct (88 mg, 0.11 mmol). The mixture rapidly turnedbrown. The suspension was then immersed in an oil bath held at 80° C.After 20 minutes the nitrogen bubbling was discontinued. After stirringfor 16 hours at 80° C., heating was discontinued, and the black reactionmixture was allowed to cool to ambient temperature. The reaction mixturewas then diluted with H₂O (100 mL) and ether (100 mL). The aqueous layerwas extracted with ether (4×20 mL), and the combined organic layers werewashed with water (2×20 mL), brine (50 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure to afford a brown oil. The oilwas azeotroped with toluene to remove any residual H₂O. The crudematerial was purified by flash chromatography eluting with a gradientfrom 0% to 14% ethyl acetate/hexane to afford2-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionicacid methyl ester (790 mg, 88% yield) as a clear bluish oil. ¹H-NMR (400MHz, CDCl₃): δ 7.77 (1H, br s), 7.72-7.67 (1H, m), 7.43-7.39 (1H, m),7.35-7.30 (1H, m), 3.65 (3H, s), 1.60 (6h, s), 1.34 (12H, s).

Preparation 13 Compounds of Formula (Pb)

A. A solution of (3-bromo-phenyl)-acetic acid (10.4 g, 48.5 mmol), inmethanol (80 mL), was treated with trimethyl orthoformate (6.5 mL, 59.4mmol). HCl gas was bubbled through the stirred solution for 10 minutes.The HCl addition was exothermic. After stirring for 15 minutes HPLCanalysis of the solution showed complete conversion to product. Afterstirring for 16 hrs at ambient temperature the solution was diluted withtoluene (100 mL) and concentrated under reduced pressure to afford abiphasic mixture. This liquid was diluted with toluene and concentratedunder reduced pressure to afford (3-bromo-phenyl)-acetic acid methylester (11.2 g, quantitative yield) as a pale yellow liquid. ¹H-NMR (400MHz, CDCl₃): δ 7.46-7.38 (2H, m), 7.23-7.18 (2H, m), 3.71 (3H, m), 3.60(2H, m).

B. Sodium hydride (2.5 g of a 60% suspension in mineral oil, 62 mmol)was placed in a flask under nitrogen. The suspension was washed withhexane (2×) then suspended in THF (30 mL), and DMF (30 mL), and cooledin an ice bath. To the cold suspension was added (3-bromo-phenyl)-aceticacid methyl ester (4.8 g, 21 mmol) dropwise as a solution in THF (10mL). The ester containing flask was then rinsed with an additionalportion of THF (10 mL) which was then added to the reaction to insurecomplete transfer. Iodomethane (4.0 mL, 64 mmol) was then added dropwiseover several minutes. The iodomethane addition led to the formation ofthick slurry at first, which slowly thinned as the reaction mixture wasstirred. The ice bath was removed and the reaction was allowed to warmto ambient temperature. After stirring for 16 hrs at ambienttemperature, HPLC analysis of a quenched aliquot (HOAc) showed severalpeaks present. There were several product peaks visible. The reactionwas quenched by the addition of methanol (10 mL). The methanol additiondid not lead to gas evolution. The reaction mixture was diluted with 1NHCl (70 mL), water (50 mL), and ether (200 mL). The aqueous layer wasextracted with ether (4×50 mL), the combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford a brown liquid. The crude material waspurified by flash chromatography eluting with a gradient from 0% to 10%ethyl acetate/hexane to afford 2-(3-bromo-phenyl)-2-methyl-propionicacid methyl ester (2.93 g, 54% yield) as a clear colorless oil. ¹H-NMR(400 MHz, CDCl₃): δ 7.49-7.47 (1H, m), 7.39-7.36 (1H, m), 7.27-7.24 (1H,m), 7.22-7.17 (1H, m), 3.66 (3H, s), 1.56 (6H, s).

Preparation 14 Compounds of Formula (R)

4-Bromo-2-chloro-1-methyl-benzene (2.5 mL, 18.7 mmoles) andN-bromosuccinimide (4.0 g, 22.5 mmoles) were dissolved into 50 mL ofCCl₄. To this stirring mix was added benzoyl peroxide (0.5 g, 2.1mmoles) and the solution was irradiated using white light. Enough lightintensity was utilized to affect gentle reflux for 2 hours. After thisperiod the mixture was cooled to ambient temperature and benzoylperoxide (0.5 g, 2.1 mmoles) was added. Again, the mix was irradiated toreflux for a period of 2 hours. After this period the reaction mix waschilled to ambient temperature and was gravity filtered. The filtratewas evaporated in vacuo and the resulting crude residue was purifiedusing flash silica chromatography (0-1% EtOAc/Hexane) to yield4-bromo-1-bromomethyl-2-chloro-benzene (3.04 g, 60%) as a clear liquid.¹H-NMR (CDCl₃): δ 7.57 (d, J=2.0 Hz, 1H), 7.39 (dd, J′=8.3 Hz, J″=1.8Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 4.53 (s, 2H).

Preparation 15 Compounds of Formula (S)

4-Bromo-1-bromomethyl-2-chloro-benzene (3.04 g, 10.7 mmoles) wasdissolved into anhydrous CH₃CN. To this mixture (under N₂ at ambienttemp) was added TMSCN (2.1 mL, 15.7 mmoles) followed by 1.0M TBAF (15.7mL, 15.7 mmoles, soln in THF). The resulting mixture was stirred atambient temperature for 15 min after which time it was evaporated invacuo to yield crude residue. The crude residue was purified using flashsilica chromatography (0-10% EtOAc/Hexane) to yield(4-bromo-2-chloro-phenyl)-acetonitrile (1.98 g, 80%) as an off-whitesolid. ¹H-NMR (CDCl₃): δ 7.60 (d, J=2.0 Hz, 1H), 7.47 (dd, J′=8.1 Hz,J″=1.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 3.79 (s, 2H).

Preparation 16 Compounds of Formula (P)

(4-Bromo-2-chloro-phenyl)-acetonitrile (1.98 g, 8.6 mmoles) wasdissolved into MeOH (50 mL) and water (5 mL), and the resultinghomogeneous mixture was chilled to 0° C. To this stirring (cold) mixturewas slowly (carefully) added concentrated HCl (25 mL). After theaddition was complete the mixture was refluxed for 16 hours. After thisperiod the reaction mixture was combined with ice and the resultingheterogeneous mixture was extracted with diethyl ether (3×50 mL). Thecombined ethereal layer was washed with brine, dried over anhydrousMgSO₄, and evaporated in vacuo to yield clean(4-bromo-2-chloro-phenyl)-acetic acid methyl ester (2.3 g, 80%). ¹H-NMR(CDCl₃): δ 7.56 (d, J=2.0 Hz, 1H), 7.37 (dd, J′=8.3 Hz, J″=2.0 Hz, 1H),7.16 (d, J=8.3 Hz, 1H), 3.73 (s, 2H), 3.72 (s, 3H).

Preparation 17 Compounds of Formula (Cb)

(4-Bromo-2-chloro-phenyl)-acetic acid methyl ester (705 mg, 2.68 mmoles)was place into a 25 mL pear-shaped flask and was sealed under nitrogen.The material was then solubilized with 20 mL of anhydrous DMSO, and theresulting solution was degassed by passing a steady stream of nitrogenthrough the solution for 10 min. In a separate round-bottom flask werecombined bis(pinacolato)diboron (0.82 g, 3.2 mmoles),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith DCM (1:1) (66 mg, 0.081 mmoles) and potassium acetate (0.79 g, 8.05mmoles) with a stirring bar under nitrogen. Following degassificationthe bromide solution was transferred to the “catalytic” mixture and theresulting mix was stirred at 90° C. for 16 hours. After this period thereaction mix was combined with 60 mL of water and was extracted withbenzene (4×15 mL). The combined benzene layer was washed with water(4×25 mL) and was dried over anhydrous Na₂SO₄. Following evaporation invacuo the crude product was purified using flash silica chromatography(0-10% EtOAc/Hexane) to yield[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]aceticacid methyl ester (502 mg, 83% yield) as a thick, clear residue. Note:TLC visualization accomplished using ceric ammonium molybdate stain.¹H-NMR (CDCl₃): δ 7.83-7.81 (br s, 1H), 7.65 (br d, J=7.6 Hz, 1H), 7.29(d, J=7.3 Hz, 1H), 3.80 (s, 2H), 3.70 (s, 3H), 1.34 (s, 12H).

Preparation 18 Compounds of Formula (BB)

A mixture of 4-bromo-2-fluoro-benzonitrile (2.6 g, 13 mmol), 10%palladium on carbon (300 mg), triphenylphosphine (300 mg, 1.2 mmol), CuI(108 mg, 0.57 mmol), and K₂CO₃ (4.55 g, 33 mmol), was prepared in1,2-dimethoxyethane (20 mL), and H₂O (20 mL). The resulting suspensionwas stirred under nitrogen for 30 minutes, and was then treated with2-methyl-but-3-yn-2-ol (2.6 mL, 27 mmol). The reaction was then heatedin an 80° C. oil bath. After stirring for 15 hours at 80° C., TLCanalysis of the reaction mixture showed some of the starting4-bromo-2-fluoro-benzonitrile remaining. A small amount of PdCl₂ wasthen added in an attempt to drive the reaction to completion. After anadditional 2 hr stirring at 80° C. the TLC had changed very little. Thereaction mixture was allowed to cool to ambient temperature, and wasfiltered through a pad of Celite. The Celite pad was washed thoroughlywith EtOAc, and the filtrate was diluted with EtOAc and H₂O. The layerswere separated and the aqueous was extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to afford a dark oil.The crude material was purified by flash chromatography eluting with agradient from 10% to 40% ethyl acetate/hexane to afford2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)-benzonitrile (2.60 g, 98%yield) as a yellow oil. ¹H-NMR (400 MHz, CDCl₃): δ 7.58-7.53 (1H, m),7.30-7.22 (2H, m), 2.10 (1H, s), 1.62 (6H, s).

Preparation 19 Compounds of Formula (CC)

To a solution of 2-fluoro-4-(3-hydroxy-3-methyl-but-1-ynyl)-benzonitrile(2.6 g, 13 mmol) in toluene (55 mL) was added NaH (53 mg of a 60%suspension in mineral oil, 1.3 mmol). The reaction mixture was heated toreflux. After refluxing for several hours, heating was discontinued, andthe cooled reaction mixture was quenched by the addition of 2M Na₂CO₃solution. The layers were separated and the toluene layer was washedwith H₂O (2×20 mL), brine (25 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford the crude product. Thecrude material was purified by flash chromatography eluting with agradient from 0% to 10% ethyl acetate/hexane to afford4-ethynyl-2-fluoro-benzonitrile (1.25 g, 66% yield). ¹H-NMR (400 MHz,CDCl₃): δ 7.61-7.57 (1H, m), 7.38-7.30 (2H, m), 3.36 (1H, s).

Preparation 20 Compounds of Formula (DD)

A solution of 4-ethynyl-2-fluoro-benzonitrile (1.29 g, 8.9 mmol) inEtOAc (30 mL) was placed in a Parr pressure bottle and palladium oncarbon (130 mg of 10% on carbon) was added. The bottle was placed on theParr hydrogenation apparatus and shaken under 10 psi of hydrogenpressure. After shaking for two hours the black suspension was filteredthrough a pad of Celite. The pad was washed thoroughly with EtOAc, andthe combined filtrates were concentrated under reduced pressure. Theresidue was taken up in toluene and concentrated under reduced pressureto afford 4-ethyl-2-fluoro-benzonitrile (1.19 g, 89% yield). ¹H-NMR (400MHz, CDCl₃): δ 7.55-7.50 (1H, m), 7.11-7.03 (2H, m), 2.72 (2H, q, J=7.6Hz), 1.26 (3H, t, J=7.6 Hz).

Preparation 21 Compounds of Formula (EE)

A solution of 4-ethyl-2-fluoro-benzonitrile (1.19 g, 8.0 mmol) in ether(70 mL) was cooled in an ice bath. To the cold, stirred solution wasadded LiAlH₄ (600 mg, 16 mmol). The suspension was then heated toreflux. After several hours at reflux, the suspension was allowed tocool to ambient temperature and was quenched by the careful addition ofH₂O (600 μL), followed by 15% aqueous NaOH (600 μL), and finally H₂O(1.8 mL). The resulting suspension was filtered, and the solids werewashed thoroughly with ether. The filtrate was concentrated underreduced pressure to afford 4-ethyl-2-fluoro-benzylamine (1.16 g, 95%yield) as a liquid. This material was used for the subsequent amideformation without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.21(1H, app t, J=7.6 Hz), 6.96-6.86 (2H, m), 3.85 (2H, s), 2.63 (2H, q,J=7.6 Hz), 1.22 (3H, t, J=7.6 Hz).

Preparation 22 Compounds of Formula (Ta)

Methyl cyanoacetate (1.16 mL, 13 mmol) and 4-ethyl-2-fluoro-benzylamine(1.15 g, 7.5 mmol) were combined in ethanol (20 mL).4-(N,N-dimethylamino)pyridine (catalytic) was added and the reaction washeated in a 60° C. oil bath. After 16 hours heating, the reaction wasconcentrated under reduced pressure to afford crude product which waspurified by flash chromatography eluting with a gradient from hexane to60% ethyl acetate/hexane to afford2-cyano-N-(4-ethyl-2-fluoro-benzyl)-acetamide (652 mg, 40% yield).¹H-NMR (400 MHz, CDCl₃): δ 7.26-7.20 (1H, m), 6.98-6.90 (2H, m), 6.39(1h, br s), 4.49 (2H, d, J=5.8 Hz), 3.38 (2H, s), 2.64 (2H, q, J=7.6Hz), 1.23 (3H, t, J=7.6 Hz).

Preparation 23 Compounds of Formula (GG)

A. Magnesium turnings (720 mg, 30 mmol) were suspended in THF (30 mL) ina 250 mL round bottom flask fitted with a thermometer. A solution of1-bromohexane (3.2 mL, 23 mmol) in THF (10 mL) was prepared after firstdrying the 1-bromohexane by passing it through a pad of activated basicalumina. About 10% of the halide solution was added to the Mgsuspension, followed by a small pellet of iodine. The addition of theiodine led to an increase in the reaction temperature indicating theinitiation of the Grignard reagent formation. The remaining halidesolution was added dropwise over ˜15 minutes. After the completion ofthe addition of the halide, the suspension was held at ˜55° C. tocomplete the formation of the Grignard reagent. While the Grignardreagent was forming, a suspension of dibenzyl oxalate (5.1 g, 19 mmol)was prepared in a mixture of ether (50 mL), and THF (15 mL). Thissuspension was cooled to <−70° C. (internal monitoring) and then treatedwith the Grignard solution prepared previously at a rate sufficient tokeep the internal temperature below −70° C. After stirring for 3 hoursat <−70° C., the reaction was quenched by the addition of saturatedaqueous NH₄Cl, followed by addition of 1 N HCl (25 mL). The coldsolution was then allowed to come to ambient temperature. After ˜64hours the reaction mixture was diluted with ether and the layers wereseparated. The acidic aqueous layer was extracted with ether (2×50 mL).The combined organic layers were washed with saturated aqueous NaHCO₃,brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford a pale brown oil. The crude material was purified byflash chromatography eluting with a gradient from 0% to 30% ethylacetate/hexane to afford 2-oxo-octanoic acid benzyl ester (3.43 g, 73%yield) as a pale yellow oil. The material was not completely pure by NMRanalysis. ¹H-NMR (400 MHz, CDCl₃): δ 7.42-7.33 (5H, m), 5.27 (2H, m),2.82 (2H, t, J=7.3 Hz), 1.66-1.56 (2H, m), 1.35-1.23 (6H, m), 0.89-0.85(3H, m).

B. A mixture of 2-oxobutyric acid (11.5 g, 113 mmol), and benzyl alcohol(14.0 mL, 135 mmol) in benzene (100 mL) was heated to reflux under aDean-Stark water separator. After refluxing for 16 hrs˜2 mL of water hadcollected in the trap (˜100% of theoretical). The reaction mixture wasallowed to cool to ambient temperature, and then concentrated underreduced pressure to afford a pale yellow oil. The crude material waspurified by flash chromatography eluting with a gradient from 0% to 15%ethyl acetate/hexane to afford 2-oxo-butyric acid benzyl ester (13.0 g,60% yield) as a clear colorless oil. ¹H-NMR (400 MHz, CDCl₃): δ7.42-7.35 (5H, m), 5.28 (5H, s), 2.87 (2H, q, J=7.2 Hz), 1.12 (3H, t,J=7.2 Hz).

Preparation 24 Compounds of Formula (HH)

In a reaction vial under nitrogen, 2-oxo-butyric acid benzyl ester (12.4g, 64.7 mmol) was treated dropwise with (diethylamino)sulfur trifluoride(10.5 mL, 79.5 mmol). The addition is exothermic and leads to adarkening of the reaction mixture. After standing at ambient temperaturefor ˜64 hours the reaction mixture was poured onto ice (˜100 g), anddiluted with ether (250 mL). The layers were separated and the aqueouswas extracted with ether (3×50 mL). The combined organic layers werewashed with saturated NaHCO₃ solution, brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford a pale orangeoil. The crude material was purified by flash chromatography elutingwith a gradient from 0% to 20% ethyl acetate/hexane to afford2,2-difluoro-butyric acid benzyl ester (13.0 g, 94% yield) as a paleyellow oil. ¹H-NMR (400 MHz, CDCl₃): δ 7.39-7.37 (5H, m), 5.29 (2H, s),2.09 (2H, t of q, J_(H-H)=7.6 Hz, J_(H-F)=16.7 Hz), 1.00 (3H, t, J=7.6Hz).

Preparation 25 Compounds of Formula (Ua)

A solution of lithium hexamethyldisilazide (2.4 mL of a 1.0M solution inTHF, 2.4 mmol) was diluted with THF (2 mL) and cooled in a −78° C. bath.To this cold solution was added 1-(4-bromo-furan-2-yl)-ethanone (317 mg,1.68 mmol) dropwise as a solution in THF (4 mL), followed by a THF (1mL) rinse of the vial and syringe to insure complete transfer. After ˜2minutes the resulting red enolate solution was treated with a solutionof 2,2-difluoro-butyric acid benzyl ester (357 mg, 1.67 mmol) in THF (4mL), followed by a THF (1 mL) rinse of the vial and syringe to insurecomplete transfer. After the completion of the addition, the coolingbath was removed and the reaction was allowed to warm to ambienttemperature. After stirring for 16 hrs at ambient temperature, thereaction was quenched by the addition of H₂O (10 mL), and diluted withether (50 mL). Phosphoric acid (2M, aqueous) was added to the mixture tobring the pH below 3. The layers were separated and the aqueous wasextracted with ether (3×20 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford a dark brown oil. The crude material was purified byflash chromatography eluting with a gradient from 0% to 30% ethylacetate/hexane to afford1-(4-bromo-furan-2-yl)-4,4-difluoro-hexane-1,3-dione (224 mg, 46% yield)as a red oil. The compound exists primarily in its' enolic form. ¹H-NMR(400 MHz, CDCl₃): δ 14.77 (1H, br s), 7.62 (1H, s), 7.27 (2H, s), 6.45(1H, s), 2.12 (2H, t of q, J_(H-H)=7.6 Hz, J_(H-F)=16.7 Hz), 1.05 (3H,t, J=7.6 Hz).

Preparation 26 Compounds of Formula (V)

To a solution of 1-(4-bromo-furan-2-yl)-4,4-difluoro-hexane-1,3-dione(220 mg, 0.75 mmol), and 2-cyano-N-(2,4-difluoro-benzyl)-acetamide (300mg, 1.4 mmol) in benzene (4 mL) was added1,8-diaza-bicycle-[5.4.0]-undec-7-ene (60 μL, 0.4 mmol). The redreaction mixture was then heated to reflux. After 3 hours, heating wasdiscontinued and the reaction was allowed to cool to ambienttemperature. After stirring at ambient temperature for 16 hours thereaction mixture was diluted with CH₂Cl₂ and purified by adsorbing thematerial onto silica gel, loading the resulting solid onto the columnand eluting with a gradient from 0% to 30% ethyl acetate/hexane toafford6-(4-bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(188 mg, 54% yield) as a yellow oil. ¹H-NMR (400 MHz, CDCl₃): δ 7.62(1H, s), 7.1-7.03 (1H, m), 6.86-6.78 (2H, m), 6.76 (1H, s), 6.64 (1H,s), 5.46 (2H, s), 2.31 (2H, t of q, J_(H-H)=7.6 Hz, J_(H-F)=16.9 Hz),1.11 (3H, t, J=7.6 Hz).

Preparation 26 Compounds of Formula (X)

Palladium catalyst([1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complexwith dichloromethane (1:1), 1.3 g, 1.59 mmol), potassium acetate (4.7 g,47.7 mmol), and bis(pinacolato)diboron (6.05 g, 23.8 mmol) were placedinto a flask and degassed with stream of N₂ for 20 min. In a separateflask, 1-(4-bromo-furan-2-yl)-ethanone (3.0 g, 15.9 mmol) was dissolvedin 30 ml anhydrous DMSO and degassed with stream of N₂ for 20 min. TheDMSO solution of 1-(4-bromo-furan-2-yl)-ethanone was added to the“catalyst” flask, and then heated at 80° C. overnight. After cooling toambient temperature, water and ethyl acetate were added to the reactionmixture. The aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel (10→30% EtOAC/Hexane, 0.25% Et₃N inhexane) to give1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-furan-2-yl]-ethanoneas a colorless oil (3.27 g, 87% yield). ¹H-NMR (400 MHz, CDCl₃): δ 1.33(s, 12H), 2.47 (s, 3H), 7.37 (d, 1H, J=0.60), 7.89 (d, 1H, J=0.68).

Preparation 27 Compounds of Formula (Ga)

To a solution of 4,6-dichloro-2-methylsulfanylpyrimidine (500 mg, 2.56mmol) in anhydrous DMF (6 mL) was added sodium ethoxide (174 mg, 2.56mmol). The reaction mixture was stirred at 70° C. for overnight. Theresulting mixture was poured into 30 mL of water and was extracted withdiethyl ether (20 mL×3) three times. The ether layer was separated anddried with anhydrous MgSO₄ and concentrated in vacuo to give crudeproduct 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine (525 mg). ¹H-NMR(CDCl₃): δ 6.39 (s, 1H), 4.43 (q, J=7.1 Hz, 2H), 2.54 (s, 3H), 1.38 (t,J=7.1H, 3H).

Preparation 28 Compounds of Formula (Y)

The crude product of Preparation 27,4-chloro-6-ethoxy-2-methylsulfanylpyrimidine, (525 mg, 2.56 mmol) wasdissolved in DMF (4 mL). To this solution was added5-acetyl-2-thiopheneboronic acid (523 mg, 3.08 mmol), PdCl₂dppf (209 mg,0.26 mmol), potassium carbonate (1.06 g, 7.69 mmol) and water (0.4 mL).The reaction mixture was heated at 80° C. under nitrogen atmosphere forovernight. The reaction mixture was cooled and poured into 30 mL ofwater and was then extracted with diethyl ether (20 mL×3) three times.The ether layer was separated and dried with anhydrous MgSO₄ andconcentrated in vacuo. The resulting crude product was purified by flashsilica column chromatography (20% ethyl acetate in hexane) to giveproduct1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone(210 mg, 28% yield over two steps). ¹H-NMR (CDCl₃): δ 7.67 (m, 2H), 6.68(s, 1H), 4.46 (q, J=7.1 Hz, 2H), 2.60 (s, 3H), 2.59 (s, 3H), 1.40 (t,J=7.1 Hz, 3H).

Preparation 29 Compounds of Formula (Z)

A.1-[5-(6-Ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone(210 mg, 0.71 mmol) was dissolved in anhydrous THF (7 mL) and cooled to−78° C. under nitrogen atmosphere. A solution of lithiumbis(trimethylsilyl)amide (0.71 mL, 1.0 M) in THF was added. The reactionmixture was stirred at −20° C. under nitrogen atmosphere for 1 h. Thereaction mixture was then cooled to −78° C. To this reaction mixture wasadded ethyl trifluoroacetate (170 μL, 1.43 mmol). The vigorously stirredsolution was allowed to warm to ambient temperature overnight. Thereaction mixture was poured into 20 mL of ice and water and was broughtto pH=3˜4 by adding 10% HCl aqueous solution. The mixture was thenextracted with diethyl ether (20 mL×3) three times. The ether layer wasseparated and dried with anhydrous MgSO₄ and concentrated in vacuo togive crude product1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-4,4,4-trifluoro-butane-1,3-dione(272 mg, 98% yield). ¹H-NMR (CDCl₃): δ 7.81 (m, 1H), 7.68 (m, 1H), 6.70(s, 1H), 6.47 (s, 1H), 4.47 (q, J=7.1 Hz, 2H), 2.61 (s, 3H), 1.41 (t,J=7.1 Hz, 3H).

B. Alternatively, lithium bis(trimethylsilyl)amide (1.0M solution inTHF, 1.1 mL, 1.1 mmol) was slowly added to a solution of1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone (240 mg,0.94 mmol) in 2 mL anhydrous THF at −78° C. under nitrogen. The mixturewas then allowed to warm to −20° C. and kept at −20° C. to −5° C. for 3hrs. After this period of time the mixture was cooled to −78° C. and toit was added ethyl trifluoroacetate (200 mg, 0.41 mmol). The mixture wasnext allowed to warm to ambient temperature overnight. 1N aqueous HClwas carefully added to adjust the pH 2. Two layers were separated andthe aqueous layer was extracted with chloroform three times. The extractwas washed with brine, dried over sodium sulfate, and concentrated invacuo to give4,4,4-trifluoro-1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-butane-1,3-dioneas a yellow solid (290 mg, 88% yield). The product was used for the nextstep without purification. 1H-NMR (400 MHz, CDCl₃): δ 6.35 (s, 1H), 7.59(dd, 1H, J=4.80, J=7.83), 8.21 (s, 1H), 8.28 (dd, 1H, J=1.77, J=3.80),8.75 (dd, 1H, J=4.80, J=1.77), 8.76 (d, 1H, J=0.51)

Preparation 30 Compounds of Formula (KK)

Sodium hydride (60% dispersion in mineral oil, 243 mg, 6.07 mmol) wassuspended in 4 mL anhydrous N,N-dimethylformamide. To this solution wasadded 4-iodo-1H-pyrazole (982 mg, 5.06 mmol) in 4 mL anhydrousN,N-dimethylformamide at 0° C. under nitrogen. The mixture was stirredat 0° C. for 15 min, and then allowed to warm to ambient temperature andstirred at the same temperature for 2 hrs. After this period of time, asolution of 2-chloro-3-trifluoromethyl-pyridine (1.01 g, 5.56 mmol) in 4mL N,N-dimethylformamide was added and the mixture was heated at 90° C.for 5 hrs. After cooling off, the mixture was poured into water andextracted with ethyl acetate three times. The combined extract waswashed with brine, dried over sodium sulfate, and concentrated in vacuoto give 2-(4-iodo-pyrazol-1-yl)-3-trifluoromethyl-pyridine as a whitesolid (1.406 g, 74% yield). The product was used for the next stepwithout purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.48 (dd, 1H, J=4.80,J=8.08), 7.79 (s, 1H), 8.21 (dd, 1H, J=1.52, J=8.08), 8.27 (s, 1H), 8.67(dd, 1H, J=1.52, J=4.80).

Preparation 31 Compounds of Formula (Ya)

Isopropylmagnesium bromide (2.0M in Et₂O, 1.11 ml, 2.22 mmol) was addedslowly to a solution of2-(4-iodo-pyrazol-1-yl)-3-trifluoromethyl-pyridine (627 mg, 1.85 mmol)in 3 mL anhydrous THF at 0° C. under nitrogen. The reaction mixture wasstirred at the same temperature for 2 hrs, and then followed by theaddition of N-methoxy-N-methyl-acetamide (286 mg, 2.78 mmol). Themixture was allowed to warm to ambient temperature overnight. Saturatedammonium chloride was added to quench the reaction. Two layers wereseparated and the aqueous layer was extracted with ethyl acetate. Thecombined extract was washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (25% EtOAC/Hexane) to give1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone as awhite solid (277 mg, 59% yield). ¹H-NMR (400 MHz, CDCl₃): δ 2.53 (s,3H), 7.57 (dd, 1H, J=5.05, J=8.08), 8.18 (s, 1H), 8.27 (dd, 1H, J=1.52,J=8.08), 8.65 (s, 1H), 8.73 (d, 1H, J=4.03).

Example 1 Compounds of Formula (Ia)

A. To a solution of6-(4-bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(75 mg, 160 μmol) and2-(3-ethylsulfanyl-5-isopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(73 mg, 240 μmol) in 1,2-dimethoxyethane (2.0 mL) was added K₂CO₃ (68mg, 490 μmol) and H₂O (200 μL).Dichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium (II)dichloromethane adduct (11 mg, 15 μmol, ˜9 mol %) was added and theresulting dark mixture was sparged with nitrogen for ˜5 minutes. Thereaction vial was sealed with a septum that had been pierced with aneedle to allow for pressure release, and immersed in an oil bath heatedto 80° C. After 5½ hours stirring at 80° C., heating was discontinuedand the reaction was allowed to stir at ambient temperature for 16 hrs.The reaction mixture was then diluted with ether and H₂O, the layerswere separated, and the aqueous was extracted with ether (3×20 mL). Thecombined ether layers were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to afford a dark oil.The crude product was purified by silica gel column chromatography byadsorbing the material onto silica gel from a CH₂Cl₂ solution, loadingthe resulting solid onto the column and eluting with a gradient from 0%to 20% ethyl acetate/hexane to afford1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-6-[4-(3-ethylsulfanyl-5-isopropyl-phenyl)-furan-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(40 mg, 44% yield) as a brown foam. ¹H-NMR (400 MHz, CDCl₃): δ 7.85 (1H,d, J=0.8 Hz), 7.18-7.15 (2H, m), 7.12-7.03 (2H, m), 7.00 (1H, d, J=0.8Hz), 6.87-6.79 (2H, m), 6.76 (1H, s), 5.56 (2H, s), 2.98 (2H, q, J=7.3Hz), 2.90 (1H, heptet, J=7.1 Hz), 2.34 (2H, t of q, J_(H-H)=7.6 Hz,J_(H-F)=16.9 Hz), 1.34 (3H, t, J=7.3 Hz), 1.27 (6H, d, J=7.1 Hz), 1.13(3H, t, J=7.3 Hz).

B. Alternatively, to6-(5-bromo-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile(134 mg, 0.28 mmol) was added2-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionicacid methyl ester (1.2 mL of a 0.47 M solution in 1,2-dimethoxyethane,0.56 mmol). The mixture was diluted with 1,2-dimethoxyethane (1.6 mL)and nitrogen was bubbled through the solution as an aqueous solution ofK₂CO₃ (0.3 mL of a 35% w/v solution in H₂O, 0.8 mmol) was added. Theaddition of the K₂CO₃ solution caused the reaction mixture to turn dark.The mixture was then treated withdichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium (II)dichloromethane adduct (21 mg, 26 μmol). After several minutes thenitrogen sparge was discontinued, and the vial was immersed in an oilbath held at 80° C. After stirring for 16 hours the dark reaction wasallowed to cool to ambient temperature, and diluted with ether (30 mL),and H₂O (10 mL). The aqueous layer was extracted with ether (1×10 ml),the combined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to afford a dark oil. The crudematerial was purified by flash chromatography eluting with a gradientfrom 0% to 20% ethyl acetate/hexane to afford2-(3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-2-methyl-propionicacid methyl ester (72 mg, 45% yield) as an orange-yellow oil. Thismaterial was not completely pure and was further purified by preparativereverse phase LC/MS chromatography on a C-18 column. The desiredfraction was collected by mass and concentrated under reduced pressureto afford2-(3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-2-methyl-propionicacid methyl ester (26 mg, 17% yield) as a yellow powder. ¹H-NMR (400MHz, CDCl₃): δ 7.52-7.50 (1H, m), 7.46-7.35 (3H, m), 7.29-7.26 (1H, m),7.12-7.05 (2H, m), 6.91-6.79 (2H, m), 6.67 (1H, s), 5.46 (2H, s), 3.68(3H, s), 1.62 (6H, s).

C. Alternatively, to6-(4-bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile(185 mg, 0.40 mmol) was added2-methyl-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]propionicacid methyl ester (1.7 mL of a 0.47 M solution in 1,2-dimethoxyethane,0.8 mmol). The mixture was diluted with 1,2-dimethoxyethane (2.3 mL) andnitrogen was bubbled through the solution as an aqueous solution ofK₂CO₃ (0.4 mL of a 35% w/v solution in H₂O, 1.0 mmol) was added. Theaddition of the K₂CO₃ solution caused the reaction mixture to turn dark.The mixture was then treated withdichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium (II)dichloromethane adduct (33 mg, 40 μmol). After several minutes thenitrogen sparge was discontinued, and the vial was immersed in an oilbath held at 80° C. After stirring for 16 hours the dark reaction wasallowed to cool to ambient temperature, and diluted with ether (30 mL),and H₂O (10 mL). The aqueous layer was extracted with ether (1×10 ml),the combined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to afford a dark oil. The crudematerial was purified by flash chromatography eluting with a gradientfrom 0% to 20% ethyl acetate/hexane to afford bright yellow productcontaining fractions from the column. Some of these fractions depositedyellow crystals upon standing. The crystals were collected and found tobe pure2-(3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-2-methyl-propionicacid methyl ester (74 mg, 33% yield). ¹H-NMR (400 MHz, CDCl₃): δ 7.89(1H, br s), 7.41-7.28 (4H, m), 7.11-7.05 (2H, m), 6.91-6.82 (3H, m),5.60 (2H, s), 3.67 (3H, s), 1.61 (6H, s).

D.6-(5-Bromo-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile(270 mg, 0.57 mmol),2-methylsulfanyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine(214 mg, 0.85 mmol), potassium carbonate (236 mg, 1.71 mmol), andtetrakis(triphenylphosphine)palladium (0) (66 mg, 0.057 mmol) were mixedwith 6 ml 9:1 DME/H₂O (v/v), then heated at 80° C. overnight. Allsolvent was removed in vacuo. The crude product was purified by columnchromatography on silica gel (10→40% EtOAC/Hexane, 0.25% Et₃N in hexane)to give1-(2,4-difluoro-benzyl)-6-[5-(6-methylsulfanyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrileas an orange solid (276 mg, 93% yield). ¹H-NMR (400 MHz, CDCl₃): δ 2.61(s, 3H), 5.45 (s, 2H), 6.66 (s, 1H), 6.82 (m, 1H), 6.88 (m, 1H), 7.09(m, 1H), 7.12 (d, 1H, J=3.9), 7.27 (m, 2H, mixed with CDCl₃), 7.64 (dd,1H, J=2.4, J=8.4), 8.67 (dd, 1H, J=2.4, J=0.8).

E.6-(4-Bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile(98 mg, 0.22 mmol),2-ethoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridine(125 mg, 0.54 mmol) (or corresponding2-ethoxy-3-trifluoromethylpyridine-5-boronic acid), potassium carbonate(149 mg, 1.08 mmol), and tetrakis(triphenylphosphine)palladium (0) (25mg, 0.1 mmol) were mixed with 2.5 ml 9:1 DME/H₂O (v/v), then heated at80° C. overnight. All solvent was removed in vacuo. The crude productwas purified by column chromatography on silica gel (10→30%EtOAC/Hexane, 0.25% Et₃N in hexane) to give1-(2,4-difluoro-benzyl)-6-[4-(6-ethoxy-5-trifluoromethyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrileas a yellow solid (29 mg, 37% yield). ¹H-NMR (400 MHz, CDCl₃): δ 1.45(t, 3H, J=7.07), 4.53 (q, 2H, J=7.07), 5.58 (s, 2H), 6.83 (s, 1H), 6.84(m, 1H), 6.87 (m, 1H), 7.04 (d, 1H, J=0.76), 7.13 (m, 1H), 7.87 (d, 1H,J=2.27), 7.90 (d, 1H, J=0.76), 8.38 (d, 1H, J=2.27).

F.6-(4-Bromo-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile620 mg, 1.3 mmoles),[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acidmethyl ester (520 mg, 1.95 mmoles),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith DCM (1:1) (32 mg, 0.39 mmoles), and K₂CO₃ (540 mg, 3.91 mmoles)were combined in 6 ml of DME/H₂O (9:1, degassed), and were stirred at85° C. for 5 hours. After this period the reaction mix was evaporatedand purified using flash silica chromatography (0-30% EtOAc/Hexane) toyield(3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-aceticacid methyl ester (365 mg, 52%) as a yellow solid. ¹H-NMR (CDCl₃): δ7.64 (br d, J=1.3 Hz, 1H), 7.39-7.35 (m, 2H), 7.33 (br d, J=1.3 Hz, 1H),7.14-7.07 (m, 1H), 6.92-6.85 (m, 1H), 6.84-6.77 (m, 1H), 6.65 (s, 1H),5.44 (s, 2H), 3.72 (s, 3H), 3.67 (s, 2H). MS (ES+): 545.3 (M+H).

Example 2 Compounds of Formula (Ia) and Oxidation

A.6-(5-Bromo-furan-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile(310 mg, 0.7 mmoles),2-(3-Ethylsulfanyl-5-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(287 mg, 0.86 mmoles), tetrakis(triphenylphosphine)palladium (0) (81 mg,0.07 mmoles), K₂CO₃ (450 mg, 3.3 mmoles) were combined in 12 ml ofDME/H₂O (9:1, degassed), and were stirred at 85° C. for 16 hours. Afterthis period the reaction mix was evaporated and purified using flashsilica chromatography (0-20% EtOAc/Hexane) to yield1-(2,4-difluoro-benzyl)-6-[5-(3-ethylsulfanyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile(0.23 g, 55%) as a yellow residue.

B.1-(2,4-Difluoro-benzyl)-6-[5-(3-ethylsulfanyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile(0.23 g, 0.39 mmoles) was dissolved into 50 mL of DCM. To this solutionat 0° C. was added 60% active m-chloroperbenzoic acid (250 mg, ˜2.25equiv.). The mix was allowed to warm to ambient temperature and wasstirred at this temperature for 30 min. After this period an additional50 mL of DCM was added and this mix was washed with 1N Na₂CO₃ (4×20 mL)and brine. The resulting DCM layer was dried over anhydrous Na₂SO₄ andwas evaporated in vacuo to yield the crude product. The crude productwas purified using flash silica chromatography (0-40% EtOAc/Hexane) toyield1-(2,4-difluoro-benzyl)-6-[5-(3-ethanesulfonyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile(205 mg, 86% yield) as a yellow solid. ¹H-NMR (CDCl₃): δ 8.26 (s, 1H),8.12 (s, 1H), 7.91 (s, 1H), 7.14-7.07 (m, 1H), 7.06 (d, J=3.8 Hz, 1H),6.98 (d, J=3.8 Hz, 1H), 6.92-6.85 (m, 1H), 6.84-6.77 (m, 1H), 6.81 (s,1H), 5.53 (s, 2H), 3.19 (q, J=7.3 Hz, 2H), 1.35 (t, J=7.3 Hz, 3H). MS(ES+): 617.1.

Example 3 Hydrolysis of Compounds of Formula (I)

A.(3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-aceticacid methyl ester (0.988 g, 1.81 mmoles) was dissolved into THF (20 mL)and water (6 mL). To this homogeneous mixture was then added LiOHhydrate (152 mg, 3.62 mmoles). This mix was then stirred at 30° C. for 2hours. After this period the reaction mixture was acidified to pH ˜3using 1H HCl and was evaporated in vacuo. The resulting residue wasextracted with DCM (3×15 mL) and the resulting organic layer was driedover anhydrous Na₂SO₄ and evaporated in vacuo to yield crude product.The crude product was purified using flash silica chromatography (0-5%MeOH/DCM) to yield(3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-aceticacid (625 mg, 65%) as a yellow solid. ¹H-NMR (CDCl₃): δ 7.64 (br d,J=1.5 Hz, 1H), 7.41-7.38 (m, 2H), 7.32-7.30 (m, 1H), 7.13-7.06 (m, 1H),6.90-6.84 (m, 1H), 6.82-6.75 (m, 1H), 6.64 (s, 1H), 5.43 (s, 2H), 3.70(s, 2H). MS (ES+): 531.1 (M+H).

Example 4 Compounds of Formula (Ib)

A.1-[5-(6-Ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-4,4,4-trifluoro-butane-1,3-dione(128 mg, 0.32 mmol) and 2,4-difluorobenzyl cyanoacetamide (82 mg, 0.39mmol) were suspended in 2 mL of benzene. To the above reaction mixturewas added DBU (24 μL, 0.16 mmol). The mixture was sealed in a vial andstirred at 90° C. for overnight. The reaction mixture was concentratedin vacuo and the resulting residue was purified by flash silica columnchromatography (30% ethyl acetate in hexane) to yield product1-(2,4-difluoro-benzyl)-6-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydropyridine-3-carbonitrile(70 mg, 38% yield). ¹H-NMR (CDCl₃): δ7.57 (m, 1H), 7.10 (m, 1H), 7.09(m, 1H), 6.87 (m, 1H), 6.79 (m, 1H), 6.65 (s, 1H), 6.64 (s, 1H), 5.41(s, 2H), 4.47 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.41 (t, J=7.1 Hz, 3H).

B.4,4,4-Trifluoro-1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-butane-1,3-dione(143 mg, 0.41 mmol) and 2-cyano-N-(2,4-difluoro-benzyl)-acetamide (86mg, 0.41 mmol) were suspended in 1.5 mL anhydrous benzene. To the abovereaction mixture was added 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU (31mg, 0.21 mmol). The mixture was heated at 90° C. under nitrogenatmosphere for overnight. After this period of time, the mixture wasevaporated in vacuo and the resulting residue was purified by columnchromatography on silica gel (35% EtOAC/Hexane) to give1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-1,2-dihydro-pyridine-3-carbonitrileas a yellow solid (78 mg, 36% yield). ¹H-NMR (400 MHz, CDCl₃): δ 5.42(s, 2H), 6.61 (s, 1H), 6.82 (m, 1H), 6.89 (m, 1H), 7.12 (m, 1H), 7.58(dd, 1H, J=4.80, J=8.08), 7.73 (s, 1H), 8.28 (dd, 1H, J=1.77, J=8.08),8.32 (s, 1H), 8.72 (dd, 1H, J=1.77, J=4.80).

Example 5 Oxidation of Compounds of Formula (I)

A. A solution of1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-6-[4-(3-ethylsulfanyl-5-isopropyl-phenyl)-furan-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(39 mg, 69 μmol) in CH₂Cl₂ was cooled in an ice bath and treated with3-chloroperoxybenzoic acid (45 mg of 77% pure material, ˜200 μmol).After several minutes stirring at 0° C., the ice bath was removed andafter an additional 15 minutes, TLC analysis of the reaction mixtureshowed the starting sulfide to be gone, and the appearance of a singleproduct spot. The reaction mixture was quenched by the addition of 10%sodium thiosulfate solution and diluted with CH₂Cl₂ (50 mL). SaturatedNaHCO₃ was added to bring the pH >8. The organic layer was dried overNa₂SO₄, filtered, and concentrated under reduced pressure to afford ayellow film. The crude product was purified by silica gel columnchromatography by adsorbing the material onto silica gel from a CH₂Cl₂solution, loading the resulting solid onto the column and eluting with agradient from 30% to 50% ethyl acetate/hexane to afford1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-6-[4-(3-ethanesulfonyl-5-isopropyl-phenyl)-furan-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(39 mg, 94% yield) as a yellow foam. ¹H-NMR (400 MHz, CDCl₃): δ 7.94(1H, s), 7.78-7.77 (1H, m), 7.72-7.71 (1H, m), 7.53-7.51 (1H, m),7.17-7.10 (1H, m), 7.07 (1H, s), 6.87-6.80 (2H, m), 6.74 (1H, s), 5.55(2H, s), 3.15 (2H, q, J=7.6 Hz), 3.10-2.99 (1H, m), 2.42-2.27 (2H, m),1.35-1.30 (9H, m), 1.14 (3H, t, J=7.6 Hz).

B.1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-propyl)-6-[4-(3-ethanesulfonyl-5-isopropyl-phenyl)-furan-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(254 mg, 0.49 mmol) was dissolved in 5 ml mixed solvent of 5:1 DCM/MeOH(v/v), and magnesium monoperoxyphthalate hydrate (MMPP, 85% tech., 627mg, 1.08 mmol) was slowly added portionwise. The reaction was completeat ambient temperature after 3 hrs. DCM was added to the reactionmixture, and the white precipitate was filtered and thoroughly washedwith DCM. The combined organic layers were washed with saturated NaHCO₃,brine, and dried over sodium sulfate. After concentration in vacuo, thecrude product was purified by column chromatography on silica gel(15→50% EtOAC/Hexane, 0.25% Et₃N in hexane) to give1-(2,4-difluoro-benzyl)-6-[5-(6-methylsulfonyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrileas a yellow solid (154 mg, 60% yield). ¹H-NMR (400 MHz, CDCl₃): δ 3.28(s, 3H), 5.43 (s, 2H), 6.66 (s, 1H), 6.81 (m, 1H), 6.90 (m, 1H), 7.14(m, 1H), 7.19 (d, 1H, J=3.9), 7.48 (d, 1H, J=3.9), 8.10 (dd, 1H, J=2.2,J=8.2), 8.17 (dd, 1H, J=0.7, J=8.2), 8.93 (dd, 1H, J=2.2, J=0.7).

C.1-(2,4-Difluoro-benzyl)-6-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydropyridine-3-carbonitrile(49 mg, 0.087 mmol) was dissolved in a mixture of dichloromethane (2 mL)and methanol (0.4 mL). To this solution was added magnesiummonoperoxyphthalate hexahydrate, MMPP, (108 mg, 0.218 mmol, 80% tech.)and the mixture was stirred at ambient temperature for overnight. Afterthis period the reaction mixture was combined with dichloromethene (20mL) and was washed with 1M NaHCO₃ (2×10 mL), and brine (10 mL). Theresulting organic layer was separated and dried over anhydrous Na₂SO₄and evaporated in vacuo to yield crude product. The crude product waspurified using flash silica chromatography (25-50% EtOAc/Hexane) toyield1-(2,4-difluorobenzyl)-6-[5-(6-ethoxy-2-methanesulfonyl-pyrimidin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile(42 mg, 80%) as a yellow solid. ¹H-NMR (CDCl₃): δ 7.72 (m, 1H), 7.14 (m,1H), 7.13 (m, 1H), 7.07 (s, 1H), 6.88 (m, 1H), 6.78 (m, 1H), 6.63 (s,1H), 5.40 (s, 2H), 4.61 (q, J=7.1 Hz, 2H), 3.36 (s, 3H), 1.46 (t, J=7.1Hz, 3H). MS (ES+): 597.2 (M+H).

Example 6

Following the procedures set forth above in the foregoing preparationsand examples and in U.S. patent application Ser. No. 10/327,813, thefollowing compounds of the invention were prepared:

-   1-(2,4-Dimethyl-benzyl)-6-[4-(3-isopropyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.3 (M+H);-   6-[4-(4-tert-Butyl-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 545.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(4-fluoro-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 507.1 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(2,4-dimethyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.4 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(2,5-dimethyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.4 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(2,6-dimethyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.4 (M+H);-   6-[4-(2-Chloro-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 523.1 (M+H);-   6-[4-(3-Chloro-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 523.2 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[3-methyl-4-(2-trifluoromethyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 557.4 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[3-methyl-4-(3-trifluoromethyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 557.4 (M+H);-   6-[4-(3-Bromo-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 553.3 (M+H);-   6-[4-(4-Bromo-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 555.2 (M+H);-   6-[4-(3-Benzyloxy-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 581.5 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(2,4-dimethyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 503.2 (M+H);-   6-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 611.4 (M+H);-   6-(4-Benzyloxy-phenyl)-1-(2,4-dichloro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 529.0 (M+H);-   1-(2,4-Dichloro-benzyl)-2-oxo-6-(4-phenoxy-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 515.0 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(4-phenoxy-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 483.0 (M+H);-   1-(2-Chloro-4-fluoro-benzyl)-2-oxo-6-(4-phenoxy-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 499.2 (M+H);-   6-(4-Benzyloxy-phenyl)-1-(2-chloro-4-fluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 513.2 (M+H);-   1-(2,4-Dichloro-benzyl)-2-oxo-4-pentafluoroethyl-6-(4-phenoxy-phenyl)-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 564.9 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-(3-isopropyl-4-phenoxy-phenyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.5 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-(3-isopropyl-4-o-tolyloxy-phenyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(2-ethyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 545.5 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(2,5-dimethyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 545.2 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(2,4-dimethyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 545.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(3,4-dimethyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 545.5 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-(3-isopropyl-4-m-tolyloxy-phenyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.2 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[3-isopropyl-4-(3-isopropyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[3-isopropyl-4-(4-isopropyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-(3-isopropyl-4-p-tolyloxy-phenyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.3 (M+H);-   6-[4-(4-tert-Butyl-phenoxy)-3-isopropyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 573.6 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[3-isopropyl-4-(4-vinyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 543.2 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(4-ethyl-2-methyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.4 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(4-ethyl-2-methyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(2-ethyl-4-methyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.2 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(2-ethyl-4-methyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.4 (M+H);-   6-(4-Benzyloxy-3-chloro-phenyl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.1 (M+H);-   6-[3-Chloro-4-(4-fluoro-phenoxy)-phenyl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 535.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-fluoro-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[4-(4-Dimethylamino-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 532.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(4-methoxy-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 519.3 (M+H);-   6-[4-(3-Cyano-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 514.4 (M+H);-   6-[4-(4-Benzyloxy-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 595.3 (M+H);-   6-[4-(3-Benzyloxy-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 595.5 (M+H);-   6-[4-(3-Cyano-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 500.4 (M+H);-   6-[4-(4-Cyano-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[4-(4-Dimethylamino-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 518.4 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(4-hydroxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 491.0 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(3-hydroxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Dimethyl-benzyl)-6-[4-(4-hexyloxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 575.5 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-{4-[4-(3-methyl-butoxy)-phenoxy]-phenyl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 561.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(3-hexyloxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 575.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-{4-[3-(3-methyl-butoxy)-phenoxy]-phenyl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 561.3 (M+H);-   (3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-phenoxy)-acetic    acid benzyl ester, MS (ES+): 639.1 (M+H);-   (4-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-phenoxy)-acetic    acid benzyl ester, MS (ES+): 639.2 (M+H);-   1-(2,4-Dimethyl-benzyl)-2-oxo-6-[4-(4-phenylamino-phenoxy)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 566.2 (M+H);-   6-[4-(4-Benzylamino-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 580.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(3-hydroxymethyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 505.1 (M+H);-   6-[4-(3-Benzyloxy-phenoxy)-3-isopropyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 623.5 (M+H);-   6-[4-(4-Benzyloxy-phenoxy)-3-isopropyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 623.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-hydroxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[4-(4-hydroxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[4-(3-Cyano-4-trifluoromethyl-phenoxy)-phenyl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 576.0 (M+H);-   4-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-2-methyl-phenoxy}-benzoic    acid methyl ester, MS (ES+): 547.3 (M+H);-   3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-2-methyl-phenoxy}-benzoic    acid methyl ester, MS (ES+): 547.4 (M+H);-   4-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoic    acid, MS (ES+): 519.2 (M+H);-   3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N-methyl-benzamide,-   3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-benzamide,    MS (ES+): 546.5 (M+H);-   1-(2,4-Dimethyl-benzyl)-2-oxo-6-{4-[3-(piperidine-1-carbonyl)-phenoxy]-phenyl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 586.1 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-{4-[3-(3-hydroxy-piperidine-1-carbonyl)-phenoxy]-phenyl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 602.4 (M+H);-   N-Benzyl-3-{4-[5-cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzamide,    MS (ES+): 608.4 (M+H);-   3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoic    acid N′-phenyl-hydrazide, MS (ES+): 609.3 (M+H);-   3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N-cyclopentyl-benzamide,    MS (ES+): 586.3 (M+H);-   3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N-methoxy-N-methyl-benzamide,    MS (ES+): 562.5 (M+H);-   3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N—((S)-1-phenyl-ethyl)-benzamide,    MS (ES+): 622.4 (M+H);-   3-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-benzamide,-   3-Benzyloxy-5-{4-[5-cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoic    acid methyl ester,-   3-Benzyloxy-5-{4-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-benzamide,    MS (ES+): 660.5 (M+H);-   3-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-5-hydroxy-N,N-dimethyl-benzamide,    MS (ES+): 570.2 (M+H);-   2-Benzyloxy-5-{4-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-benzamide,    MS (ES+): 660.3 (M+H);-   5-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-2-hydroxy-N,N-dimethyl-benzamide,    MS (ES+): 570.7 (M+H);-   3-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N-methyl-benzamide,-   N-tert-Butyl-3-{4-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzamide,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{4-[3-(piperidine-1-carbonyl)-phenoxy]-phenyl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   (S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-propionic    acid methyl ester, MS (ES+): 604.3 (M+H);-   (R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-propionic    acid methyl ester, MS (ES+): 604.1 (M+H);-   (S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-methyl-butyric    acid methyl ester, MS (ES+): 632.3 (M+H);-   (R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-methyl-butyric    acid methyl ester, MS (ES+): 632.5 (M+H);-   (S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-4-methyl-pentanoic    acid methyl ester, MS (ES+): 646.5 (M+H);-   (R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-4-methyl-pentanoic    acid methyl ester, MS (ES+): 646.4 (M+H);-   (S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-phenyl-propionic    acid methyl ester, MS (ES+): 680.3 (M+H);-   (R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-phenyl-propionic    acid methyl ester, MS (ES+): 680.3 (M+H);-   (S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-(1H-imidazol-4-yl)-propionic    acid methyl ester, MS (ES+): 670.1 (M+H);-   (R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-(1H-imidazol-4-yl)-propionic    acid methyl ester, MS (ES+): 670.2 (M+H);-   (S)-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-phenyl-acetic    acid methyl ester, MS (ES+): 666.5 (M+H);-   (R)-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-phenyl-acetic    acid methyl ester, MS (ES+): 666.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(4-methylsulfanyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 521.1 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-{4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-phenyl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 620.2 (M+H);-   3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-thiobenzamide,    MS (ES+): 562.4 (M+H);-   6-[3-Chloro-4-(4-methanesulfonyl-phenoxy)-phenyl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 595.4 (M+H);-   1-(2,5-Diethyl-thiazol-4-ylmethyl)-2-oxo-6-(4-phenoxy-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-(4′-methanesulfonyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-(4′-methanesulfonyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-(4′-ethylsulfanyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 595.6 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(4′-ethanesulfonyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 627.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(4′-methylsulfanyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 581.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(5′-methylsulfanyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 581.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(4′-methylsulfanyl-3′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 581.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(5′-methylsulfanyl-3′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 581.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(4′-methanesulfonyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 614.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(4′-methanesulfonyl-3′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 614.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(3′-methanesulfonyl-5′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 613.1 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[5′-trifluoromethyl-3′-(2-trimethylsilanyl-ethanesulfonyl)-biphenyl-3-yl]-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 699.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(3′-ethanesulfonyl-5′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 627.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-2-sulfonyl)-5′-trifluoromethyl-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 641.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(4′-ethoxy-3′-methanesulfonyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[5′-(propane-1-sulfinyl)-3′-trifluoromethyl-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 625.3 (M+H);-   6-[5′-(Butane-1-sulfinyl)-3′-trifluoromethyl-biphenyl-3-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5′-phenylmethanesulfinyl-3′-trifluoromethyl-biphenyl-3-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 673.4 (M+H);-   6-(5′-Cyclopropylmethanesulfinyl-3′-trifluoromethyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 637.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[5′-(propane-1-sulfinyl)-3′-trifluoromethyl-biphenyl-4-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 624.9 (M+H);-   6-[5′-(Butane-1-sulfinyl)-3′-trifluoromethyl-biphenyl-4-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 639.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5′-phenylmethanesulfinyl-3′-trifluoromethyl-biphenyl-4-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 673.0 (M+H);-   6-(5′-Cyclopropylmethanesulfinyl-3′-trifluoromethyl-biphenyl-4-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 637.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(5′-ethanesulfinyl-3′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 611.1 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-2-sulfinyl)-5′-trifluoromethyl-biphenyl-4-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 625.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-1-sulfonyl)-5′-trifluoromethyl-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 641.4 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-1-sulfonyl)-5′-trifluoromethyl-biphenyl-4-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 641.1 (M+H);-   6-[3′-(Butane-1-sulfonyl)-5′-trifluoromethyl-biphenyl-3-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 655.2 (M+H);-   6-[3′-(Butane-1-sulfonyl)-5′-trifluoromethyl-biphenyl-4-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 655.1 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(3′-phenylmethanesulfonyl-5′-trifluoromethyl-biphenyl-3-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 689.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(3′-phenylmethanesulfonyl-5′-trifluoromethyl-biphenyl-4-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 689.3 (M+H);-   6-(3′-Cyclopropylmethanesulfonyl-5′-trifluoromethyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 653.3 (M+H);-   6-(3′-Cyclopropylmethanesulfonyl-5′-trifluoromethyl-biphenyl-4-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-(3′-ethanesulfonyl-5′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-2-sulfonyl)-5′-trifluoromethyl-biphenyl-4-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-(5′-isopropyl-3′-methanesulfonyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 587.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(5′-ethyl-3′-methanesulfonyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 573.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(3′-ethanesulfonyl-5′-isopropyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 601.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(3′-methanesulfonyl-5′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 613.1 (M+H);-   6-(3′-Acetyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-(4′-Acetyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-carboxylic    acid amide,-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylic    acid amide,-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-carboxylic    acid dimethylamide,-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylic    acid dimethylamide,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(pyrrolidine-1-carbonyl)-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[4′-(piperidine-1-carbonyl)-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-carboxylic    acid ethylamide,-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylic    acid methylamide,-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylic    acid phenylamide,-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylic    acid benzylamide,-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-5-isopropyl-biphenyl-3-carboxylic    acid methyl ester, MS (ES+): 567.3 (M+H);-   3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-5-isopropyl-biphenyl-3-carboxylic    acid methyl ester;-   {3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-yl}-acetic    acid, MS (ES+): 525.5 (M+H);-   {4′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-yl}-acetic    acid, MS (ES+): 525.4 (M+H);-   {3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-yl}-acetic    acid, MS (ES+): 525.3 (M+H);-   {4′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-yl}-acetic    acid, MS (ES+): 591.2 (M+H);-   {3-Chloro-3′-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-yl}-acetic    acid methyl ester, MS (ES+): 573.2 (M+H);-   {3-Chloro-3′-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-yl}-acetic    acid, MS (ES+): 559.1 (M+H);-   6-(3′,5′-Bis-trifluoromethyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-(3′-Chloro-4′-ethoxy-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-(3′,4′-dimethoxy-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-(3′-Chloro-4′-ethoxy-biphenyl-4-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(3-phenylethynyl-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 491.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(4-phenylethynyl-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 491.1 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[3-((E)-styryl)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 493.4 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[4-((E)-styryl)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 493.4 (M+H);-   6-(3′-Amino-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-(4′-ethoxy-3′-nitro-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-(3′-Amino-4′-ethoxy-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   {3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-4-ethoxy-biphenyl-3-yl}-carbamic    acid tert-butyl ester,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5-m-tolyl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 487.2 (M+H);-   1-(2,4-Dichloro-benzyl)-2-oxo-6-(5-m-tolyl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 519.2 (M+H);-   1-(2,4-Dimethyl-benzyl)-2-oxo-6-(5-m-tolyl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 479.1 (M+H);-   6-[5-(3-Chloro-4-ethoxy-phenyl)-thiophen-2-yl]-1-(2,4-dichloro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 585.1 (M+H);-   1-(2,4-Dichloro-benzyl)-6-[5-(4-methoxy-3-methyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 549.2 (M+H);-   1-(2,4-Dichloro-benzyl)-2-oxo-4-trifluoromethyl-6-[5-(2,4,5-trimethyl-phenyl)-thiophen-2-yl]-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 547.4 (M+H);-   1-(2,4-Dichloro-benzyl)-6-[5-(4-methoxy-2-methyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[5-(3,5-Bis-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(2,4-dichloro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 640.9 (M+H);-   1-(2,4-Dichloro-benzyl)-2-oxo-6-(5-o-tolyl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 519.1 (M+H);-   1-(2,4-Dichloro-benzyl)-6-[5-(3,4-dimethoxy-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 565.3 (M+H);-   1-(2,4-Dichloro-benzyl)-6-[5-(3,5-dichloro-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[5-(3,5-Dichloro-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5-o-tolyl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 487.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3,4-dimethoxy-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 533.2 (M+H);-   6-[5-(3-Chloro-4-ethoxy-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 551.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methoxy-3-methyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.3 (M+H);-   6-[5-(2-Bromo-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 488.4 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[5-(3-trifluoromethyl-phenyl)-thiophen-2-yl]-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 541.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(2-fluoro-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methoxy-3,5-dimethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-hydroxy-3,5-dimethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.0 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-hydroxymethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 502.9 (M+H);-   6-[4-(3,5-Bis-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[4-(3-Chloro-4-ethoxy-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[4-(3,4-dimethoxy-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methoxy-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 571.0 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-fluoro-4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5-phenylethynyl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 497.0 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(4-phenylethynyl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 497.1 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[5-((E)-styryl)-thiophen-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 499.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[4-((E)-styryl)-thiophen-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 499.4 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5-phenethyl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 501 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-hydroxymethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[4-(4-methoxy-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 570.9 (M+H);-   6-[5-(3-Chloro-4-methyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 521.1 (M+H);-   6-[5-(3-Chloro-4-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 575.3 (M+H);-   6-[4-(3-Chloro-4-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 574.9 (M+H);-   6-[4-(3-Chloro-4-methyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 521.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-methoxy-4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 571.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethoxy-4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 585.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-ethoxy-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 585.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-ethoxy-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 585.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethoxy-4-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 585.2 (M+H);-   6-{5-[3-Chloro-4-(2,2,2-trifluoro-ethoxy)-phenyl]-thiophen-2-yl}-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 605.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-fluoro-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-fluoro-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 558.9 (M+H);-   6-[5-(3-Chloro-4-hydroxy-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 523.2 (M+H);-   6-{5-[3-Chloro-4-(2-hydroxy-ethoxy)-phenyl]-thiophen-2-yl}-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 567.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethoxy-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 585.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethoxy-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 585.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-isopropoxy-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 599.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-isopropoxy-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 599.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethoxy-5-ethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 545.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethoxy-5-ethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 545.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethyl-5-isopropoxy-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethyl-5-isopropoxy-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.2 (M+H);-   1-(2,4-Dichloro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 583.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 551.1 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 543.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-ethanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 565.1 (M+H);-   1-(2,4-Difluoro-benzyl)-3-dimethylaminomethyl-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-4-trifluoromethyl-1H-pyridin-2-one,    MS (ES+): 583.5 (M+H);-   1-(2,4-Dichloro-benzyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 583.3 (M+H);-   N-{1-(2,4-Difluoro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridin-3-ylmethyl}-methanesulfonamide,    MS (ES+): 633.3 (M+H);-   3-Diethylaminomethyl-1-(2,4-difluoro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-4-trifluoromethyl-1H-pyridin-2-one,    MS (ES+): 611.4 (M+H);-   N-{1-(2,4-Difluoro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridin-3-ylmethyl}-guanidine,    MS (ES+): 597.5 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 551.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 565.4 (M+H);-   6-[5-(3,5-Bis-methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 628.9 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 587.5 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-methylsulfanyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 587.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 586.8 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-methylsulfanyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 587.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methyl-3-methylsulfanyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 533.8 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methanesulfinyl-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 518.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(5-methanesulfinyl-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[4-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 620.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-methanesulfonyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 619.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-ethoxy-3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 595.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{5-[3-(propane-1-sulfinyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-{5-[3-(Butane-1-sulfinyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[5-(3-phenylmethanesufinyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[5-(3-Cyclopropylmethanesulfinyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethanesulfinyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{4-[3-(propane-1-sulfinyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-{4-[3-(Butane-1-sulfinyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[4-(3-phenylmethanesulfinyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[4-(3-Cyclopropylmethanesulfinyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethanesulfinyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{4-[3-(propane-2-sulfinyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{5-[3-(propane-1-sulfonyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-{5-[3-(Butane-1-sulfonyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 661.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[5-(3-phenylmethanesulfonyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 695.1 (M+H);-   6-[5-(3-Cyclopropylmethanesulfonyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethanesulfonyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{4-[3-(propane-1-sulfonyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-{4-[3-(Butane-1-sulfonyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[4-(3-Cyclopropylmethanesulfonyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethanesulfonyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{4-[3-(propane-2-sulfonyl)-5-trifluoromethyl-phenyl]-thiophen-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[5-(3-isopropyl-5-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 593.0 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-isopropyl-5-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 593.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 619.2 (M+H);-   6-[5-(3-Ethanesulfonyl-phenyl)-thiophen-2-yl]-1-(2-fluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 547.3 (M+H);-   1-(2-Chloro-benzyl)-6-[5-(3-ethanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 563.2 (M+H);-   1-(2-Fluoro-benzyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 533.3 (M+H);-   1-(2-Chloro-benzyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[5-(3-Ethanesulfonyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(2-fluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 615.0 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethyl-5-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 679.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethyl-5-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 679.3 (M+H);-   1-(2-Chloro-benzyl)-6-[5-(3-ethanesulfonyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 631.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-acetic    acid, MS (ES+): 515.2 (M+H);-   1-(2-Chloro-benzyl)-6-[5-(3-isopropyl-5-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 591.1 (M+H);-   1-(2-Fluoro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 533.2 (M+H);-   1-(2-Chloro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 549.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethanesulfonyl-5-isopropyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 607.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethanesulfonyl-5-isopropyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 607.3 (M+H);-   6-[5-(3-Ethanesulfonyl-phenyl)-thiophen-2-yl]-1-(4-ethyl-2-fluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 575.2 (M+H);-   1-(4-Ethyl-2-fluoro-benzyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(4-Ethyl-2-fluoro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 561.2 (M+H);-   6-[5-(3-Ethanesulfonyl-5-trifluoromethyl-phenyl)-thiophen-2-yl]-1-(4-ethyl-2-fluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(4-Ethyl-2-fluoro-benzyl)-6-[5-(3-isopropyl-5-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 603.2 (M+H);-   4-(1,1-Difluoro-propyl)-1-(2-fluoro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 543.3 (M+H);-   4-(1,1-Difluoro-propyl)-1-(2-fluoro-benzyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 543.3 (M+H);-   4-(1,1-Difluoro-propyl)-6-[5-(3-ethanesulfonyl-5-isopropyl-phenyl)-thiophen-2-yl]-1-(2-fluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 599.2 (M+H);-   6-[5-(3-tert-Butyl-5-methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 607.2 (M+H);-   6-[4-(3-tert-Butyl-5-methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 607.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethanesulfonyl-5-ethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 593.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-{5-[3-ethyl-5-(propane-1-sulfonyl)-phenyl]-thiophen-2-yl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 607.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-{5-[3-ethyl-5-(propane-2-sulfonyl)-phenyl]-thiophen-2-yl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 607.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethanesulfonyl-5-ethyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 593.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-{4-[3-ethyl-5-(propane-1-sulfonyl)-phenyl]-thiophen-2-yl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 607.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-{4-[3-ethyl-5-(propane-2-sulfonyl)-phenyl]-thiophen-2-yl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 607.5 (M+H);-   1-(4-Chloro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 579.0 (M+H);-   6-[5-(3-Ethanesulfonyl-5-isopropyl-phenyl)-thiophen-2-yl]-1-(2-fluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 589.3 (M+H);-   1-(2-Chloro-benzyl)-6-[5-(3-ethanesulfonyl-5-isopropyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 605.4 (M+H);-   1-(4-Chloro-benzyl)-6-[5-(3-ethanesulfonyl-5-isopropyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 605.6 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-5-isopropyl-phenyl)-acetic    acid, MS (ES+): 573.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-5-isopropyl-phenyl)-acetic    acid, MS (ES+): 573.3 (M+H);-   1-(4-Chloro-benzyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 549.4 (M+H);-   1-(2,4-Difluoro-benzyl)-4-(1,1-difluoro-heptyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 617.0 (M+H);-   1-(2,4-Difluoro-benzyl)-4-(1,1-difluoro-heptyl)-6-[5-(3-ethanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 631.4 (M+H);-   1-(2,4-Difluoro-benzyl)-4-(1,1-difluoro-heptyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 617.4 (M+H);-   1-(2,4-Difluoro-benzyl)-4-(1,1-difluoro-3-methyl-butyl)-6-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 589.3 (M+H);-   1-(2,4-Difluoro-benzyl)-4-(1,1-difluoro-3-methyl-butyl)-6-[5-(3-ethanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 603.3 (M+H);-   1-(2,4-Difluoro-benzyl)-4-(1,1-difluoro-3-methyl-butyl)-6-[5-(4-methanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 589.4 (M+H);-   4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-benzenesulfonamide,    MS (ES+): 552.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-formyl-4-methoxy-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   Carbonic acid tert-butyl ester    4-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl    ester, MS (ES+): 589.4 (M+H);-   6-[5-(3-Chloro-4-cyano-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.8 (M+H);-   6-[5-(3-Cyano-4-ethoxy-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 547.4 (M+H);-   6-[4-(3-Cyano-4-ethoxy-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 526.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-ethoxy-3-nitro-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[5-(3-Amino-4-ethoxy-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   (2-Chloro-4-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenoxy)-acetic    acid ethyl ester, MS (ES+): 609.2 (M+H);-   (2-Chloro-4-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenoxy)-acetic    acid, MS (ES+): 581.3 (M+H);-   6-[5-(4-Amino-3-chloro-phenyl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 522.2 (M+H);-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-2-ethoxy-phenyl)-carbamic    acid tert-butyl ester,-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-2-ethoxy-phenyl)-carbamic    acid tert-butyl ester,-   4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-benzoic    acid methyl ester, MS (ES+): 531.2 (M+H);-   3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-benzoic    acid methyl ester, MS (ES+): 530.9 (M+H);-   3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-benzoic    acid,-   4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-benzoic    acid,-   3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-5-isopropyl-benzoic    acid methyl ester, MS (ES+): 573.2 (M+H);-   3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-5-isopropyl-benzoic    acid methyl ester, MS (ES+): 573.2 (M+H);-   3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-thiobenzamide,    MS (ES+): 562.4 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-acetic    acid,-   (4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-acetic    acid,-   (4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-acetic    acid,-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 545.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 545.3 (M+H);-   (4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 545.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-5-isopropoxy-phenyl)-acetic    acid, MS (ES+): 589.2 (M+H);-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-2-methoxy-phenyl)-acetic    acid methyl ester, MS (ES+): 575.4 (M+H);-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-2-methoxy-phenyl)-acetic    acid methyl ester,-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-5-isopropoxy-phenyl)-acetic    acid methyl ester, MS (ES+): 603.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-4-fluoro-phenyl)-acetic    acid methyl ester, MS (ES+): 563.3 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-4-methoxy-phenyl)-acetic    acid methyl ester, MS (ES+): 575.1 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-5-isopropoxy-phenyl)-acetic    acid, MS (ES+): 589.2 (M+H);-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-2-methoxy-phenyl)-acetic    acid, MS (ES+): 561.2 (M+H);-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-2-methoxy-phenyl)-acetic    acid, MS (ES+): 561.3 (M+H);-   2-(3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-2-methyl-propionic    acid methyl ester, MS (ES+): 573.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-4-fluoro-phenyl)-acetic    acid methyl ester, MS (ES+): 563.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-4-methoxy-phenyl)-acetic    acid, MS (ES+): 561.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-heptyl)-6-oxo-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 611.5 (M+H);-   (2-Chloro-4-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 579.3 (M+H);-   (2-Chloro-4-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 579.4 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-acetic    acid tert-butyl ester, MS (ES+): 587 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-4-(1,1-difluoro-3-methyl-butyl)-6-oxo-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 583 (M+H);-   3-(3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-propionic    acid methyl ester, MS (ES+): 559.1 (M+H);-   3-(3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-propionic    acid methyl ester, MS (ES+): 559.2 (M+H);-   3-(4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-phenyl)-propionic    acid methyl ester, MS (ES+): 559.1 (M+H);-   3-(4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-propionic    acid methyl ester, MS (ES+): 558.7 (M+H);-   6-[5-(3,5-Bis-trifluoromethyl-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 593 (M+H);-   6-[5-(2-Chloro-5-trifluoromethyl-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3,4-dimethoxy-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-hydroxy-3-methoxy-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 503.3 (M+H);-   6-[4-(3,5-Bis-trifluoromethyl-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 593.2 (M+H);-   6-[4-(3-Chloro-4-ethoxy-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 535.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methoxy-3-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 555.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-fluoro-4-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 543.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-fluoro-3-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 542.9 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-methoxy-3-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 555.2 (M+H);-   6-[4-(3-Chloro-4-methyl-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 504.8 (M+H);-   6-[4-(3-Chloro-4-trifluoromethyl-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.1 (M+H);-   6-[5-(3-Chloro-4-trifluoromethyl-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-fluoro-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 543.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-fluoro-3-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 543.4 (M+H);-   6-[5-(3-Chloro-4-methyl-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 504.9 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-ethoxy-3-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 569.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethoxy-4-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 569.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethoxy-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 569.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-isopropoxy-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 583.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethoxy-5-ethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 529.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethyl-5-isopropoxy-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 543.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methanesulfonyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 535.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methylsulfanyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 503.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethanesulfonyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 549.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-methanesulfonyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 535.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 570.9 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-methylsulfanyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 571.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 571.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-methylsulfanyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 571.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methyl-3-methylsulfanyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 518.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 604.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 604.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-methanesulfonyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 603.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-methanesulfonyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 603.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{5-[3-(propane-2-sulfonyl)-5-trifluoromethyl-phenyl]-furan-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 631.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethanesulfonyl-5-trifluoromethyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 616.9 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{4-[3-(propane-1-sulfonyl)-5-trifluoromethyl-phenyl]-furan-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 630.9 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{4-[3-(propane-2-sulfonyl)-5-trifluoromethyl-phenyl]-furan-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 631.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-{5-[3-(propane-1-sulfonyl)-5-trifluoromethyl-phenyl]-furan-2-yl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 630.9 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-isopropyl-5-methanesulfonyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 577.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethyl-5-methanesulfonyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 563.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-ethyl-5-methanesulfonyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 563 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(3-ethanesulfonyl-5-isopropyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 591.2 (M+H);-   1-(2-Fluoro-benzyl)-6-[4-(4-methanesulfonyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.4 (M+H);-   6-[4-(3-tert-Butyl-5-methanesulfonyl-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 591.2 (M+H);-   1-(2-Fluoro-benzyl)-6-[4-(3-methanesulfonyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.2 (M+H);-   6-[4-(3-Ethanesulfonyl-phenyl)-furan-2-yl]-1-(2-fluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-{4-[3-ethyl-5-(propane-1-sulfonyl)-phenyl]-furan-2-yl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 591.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-{4-[3-ethyl-5-(propane-2-sulfonyl)-phenyl]-furan-2-yl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 591.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(3-methanesulfonyl-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 535.4 (M+H);-   6-[4-(3-Chloro-4-cyano-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 516.5 (M+H);-   6-[4-(3-Cyano-4-ethoxy-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 526.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(4-ethoxy-3-nitro-phenyl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[4-(4-Amino-3-chloro-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 506.2 (M+H);-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-2-ethoxy-phenyl)-carbamic    acid tert-butyl ester,-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-2-yl}-2-ethoxy-phenyl)-carbamic    acid tert-butyl ester,-   3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-5-isopropyl-benzoic    acid methyl ester, MS (ES+): 557.3 (M+H);-   6-[4-(3-Amino-4-ethoxy-phenyl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-acetic    acid,-   (4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-acetic    acid,-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-5-isopropyl-phenyl)-acetic    acid, MS (ES+): 557.4 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 529.4 (M+H);-   (4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 529.3 (M+H);-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-2-methoxy-phenyl)-acetic    acid methyl ester, MS (ES+): 559.3 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-5-isopropoxy-phenyl)-acetic    acid, MS (ES+): 573.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-4-methoxy-phenyl)-acetic    acid methyl ester, MS (ES+): 559.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-4-fluoro-phenyl)-acetic    acid methyl ester, MS (ES+): 547.4 (M+H);-   (5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-2-methoxy-phenyl)-acetic    acid, MS (ES+): 545.3 (M+H);-   (2-Chloro-4-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-acetic    acid methyl ester, MS (ES+): 563.2 (M+H);-   (3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-benzyl)-carbamic    acid tert-butyl ester, MS (ES+): 602.4 (M+H);-   3-(3-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-propionic    acid methyl ester, MS (ES+): 543.3 (M+H);-   3-(4-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-phenyl)-propionic    acid methyl ester, MS (ES+): 543.5 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(3-thiazol-2-yl-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 474.2 (M+H);-   5-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-1H-indole-2-carboxylic    acid ethyl ester,-   1-(2,4-Dimethyl-benzyl)-6-[4-(1H-indol-5-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 514.4 (M+H);-   1-(2,4-Dimethyl-benzyl)-2-oxo-6-[4-(pyrimidin-2-yloxy)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 477.1 (M+H);-   1-(2,4-Dimethyl-benzyl)-2-oxo-6-[4-(pyrazin-2-yloxy)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 477.2 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(4,6-dimethyl-pyrimidin-2-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 505.3 (M+H);-   1-(2,4-Dichloro-benzyl)-2-oxo-6-[4-(pyrazin-2-yloxy)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 516.9 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[4-(pyrazin-2-yloxy)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 485.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(3,6-dimethyl-pyrazin-2-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 505.3 (M+H);-   6-[4-(3-Chloro-pyrazin-2-yloxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 511.2 (M+H);-   6-[4-(6-Chloro-pyrazin-2-yloxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 511.2 (M+H);-   2-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-nicotinonitrile,    MS (ES+): 501.3 (M+H);-   2-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-6-methyl-nicotinonitrile,    MS (ES+): 515.4 (M+H);-   1-(2,4-Dimethyl-benzyl)-2-oxo-4-trifluoromethyl-6-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 544.3 (M+H);-   1-(2,4-Dichloro-benzyl)-6-[4-(1H-indol-5-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 554.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(1H-indol-5-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 522.1 (M+H);-   1-(2-Chloro-4-fluoro-benzyl)-6-[4-(1H-indol-5-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 538.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[3-methyl-4-(pyrazin-2-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 491.3 (M+H);-   6-[4-(3-Chloro-pyrazin-2-yloxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 525.4 (M+H);-   6-[4-(6-Chloro-pyrazin-2-yloxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 525.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(3,6-dimethyl-pyrazin-2-yloxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 519.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[3-isopropyl-4-(pyrazin-2-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 519.3 (M+H);-   6-[4-(3-Chloro-pyrazin-2-yloxy)-3-isopropyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 553.4 (M+H);-   6-[4-(6-Chloro-pyrazin-2-yloxy)-3-isopropyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 553.4 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(3,6-dimethyl-pyrazin-2-yloxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 547.3 (M+H);-   2-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-2-isopropyl-phenoxy}-6-methyl-nicotinonitrile,    MS (ES+): 557.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[4-(pyrimidin-2-yloxy)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 485.1 (M+H);-   3-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-pyrazine-2-carbonitrile,    MS (ES+): 510.1 (M+H);-   2-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-6-methyl-nicotinonitrile,    MS (ES+): 523.2 (M+H);-   2-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-nicotinonitrile,    MS (ES+): 509.2 (M+H);-   6-[4-(6-Chloro-pyrazin-2-yloxy)-phenyl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 519.3 (M+H);-   6-[3-Chloro-4-(pyrimidin-2-yloxy)-phenyl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 519.2 (M+H);-   6-[3-Chloro-4-(pyrazin-2-yloxy)-phenyl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 519.2 (M+H);-   2-{2-Chloro-4-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-nicotinonitrile,    MS (ES+): 543.3 (M+H);-   1-(2,4-Dimethyl-benzyl)-6-[4-(1H-indol-5-yloxy)-3,5-dimethyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[4-(1H-indol-5-yl)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 506.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[3-(1H-indol-5-yl)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 506.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(3-pyridin-3-yl-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(3-pyridin-4-yl-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Dimethyl-benzyl)-6-[4-(1H-indol-5-yloxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 552.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[4-(3-trifluoromethyl-pyridin-2-yloxy)-phenyl]-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 552.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[4-(6-trifluoromethyl-pyridin-2-yloxy)-phenyl]-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 552.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(1H-indol-6-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-4-trifluoromethyl-nicotinic    acid methyl ester, MS (ES+): 610.1 (M+H);-   1-(2,4-Dichloro-benzyl)-6-[4-(1-methyl-1H-indol-5-yloxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   5-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-1H-indole-2-carboxylic    acid ethyl ester, MS (ES+): 586.2 (M+H);-   1-(2,4-Dimethyl-benzyl)-2-oxo-6-[4-(piperidin-4-yloxy)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(3-piperidin-1-yl-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 474.2 (M+H);-   4-{3-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenyl}-piperazine-1-carboxylic    acid tert-butyl ester, MS (ES+): 575.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(4-piperidin-1-yl-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 474.3 (M+H);-   4-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenyl}-piperazine-1-carboxylic    acid tert-butyl ester, MS (ES+): 575.4 (M+H);-   4-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-piperidine-1-carboxylic    acid tert-butyl ester, MS (ES+): 582.3 (M+H);-   6-(3-Benzo[1,3]dioxol-5-yl-phenyl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-(4-Benzo[1,3]dioxol-5-yl-phenyl)-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[5-(6-methoxy-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 488.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(2,4-dimethoxy-pyrimidin-5-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 519.5 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(4-pyridin-4-yl-furan-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 458.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-methylsulfanyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 504.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-methanesulfonyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 536.2 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-2-ethoxy-nicotinonitrile,    MS (ES+): 527.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethoxy-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 502.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-isopropoxy-5-trifluoromethyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 584.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-methanesulfonyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 536 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-2-ethoxy-nicotinic    acid ethyl ester, MS (ES+): 574.1 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-2-yl}-2-ethoxy-nicotinic    acid ethyl ester, MS (ES+): 574 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(5-methyl-6-methylsulfanyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 518.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 550.3 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-furan-3-yl}-2-methanesulfonyl-nicotinic    acid methyl ester, MS (ES+): 594.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(5-isopropenyl-6-methylsulfanyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 544.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethoxy-5-isopropenyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 542.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(5-isopropenyl-6-methanesulfonyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 576.3 (M+H);-   1-(2,4-Difluoro-benzyl)-4-(1,1-difluoro-propyl)-6-[4-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-furan-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 560.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethylsulfanyl-5-methyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 532.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethoxy-5-isopropyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 544.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(5-isopropyl-6-methanesulfonyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 578.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethanesulfonyl-5-methyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 564.2 (M+H);-   6-[4-(2-Chloro-pyridin-4-yl)-furan-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 492.2 (M+H);-   1-(2-Fluoro-benzyl)-6-[4-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 532.4 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[4-(6-piperazin-1-yl-pyridin-3-yl)-furan-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 542.4 (M+H);-   6-(5-Benzo[1,3]dioxol-5-yl-furan-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 501.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-furan-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 515.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5-pyridin-3-yl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 474.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5-pyridin-4-yl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 474 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(4-pyridin-3-yl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(4-pyridin-4-yl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-[4-(1H-indol-5-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5-pyridin-2-yl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 474.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-methoxy-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 504.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(2,4-dimethoxy-pyrimidin-5-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 535 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(5-pyrimidin-5-yl-thiophen-2-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 475.2 (M+H);-   6-[5-(2,6-Bis-trifluoromethyl-pyridin-4-yl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 610.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-ethoxy-5-trifluoromethyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 586.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethoxy-5-trifluoromethyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 586.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-methylsulfanyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 520.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-methanesulfonyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 552.2 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-2-ethoxy-nicotinonitrile,    MS (ES+): 543.1 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-2-ethoxy-nicotinonitrile,    MS (ES+): 543.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethoxy-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 518.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-ethoxy-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 518.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-isopropoxy-5-trifluoromethyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 600.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[5-(1-oxy-pyridin-4-yl)-thiophen-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 490.2 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-2-ethoxy-nicotinic    acid ethyl ester, MS (ES+): 590.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(5-methyl-6-methylsulfanyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 534.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(5-methyl-6-methylsulfanyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 534.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 566.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 566.2 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-2-methylsulfanyl-nicotinic    acid methyl ester, MS (ES+): 578.3 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-2-methylsulfanyl-nicotinic    acid methyl ester, MS (ES+): 578.2 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-2-methanesulfonyl-nicotinic    acid methyl ester, MS (ES+): 610.2 (M+H);-   5-{5-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-2-methanesulfonyl-nicotinic    acid methyl ester, MS (ES+): 610.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(5-isopropenyl-6-methylsulfanyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 560.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(5-isopropenyl-6-methanesulfonyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 592.2 (M+H);-   1-(2-Fluoro-benzyl)-6-[5-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 548.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-ethoxy-5-isopropenyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 558.3 (M+H);-   1-(4-Ethyl-2-fluoro-benzyl)-6-[5-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 576.2 (M+H);-   1-(2-Chloro-benzyl)-6-[5-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 564.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethoxy-5-isopropenyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 558.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-ethoxy-5-isopropyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 560.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-ethylsulfanyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 548.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethoxy-5-isopropyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 560.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(5-isopropyl-6-methanesulfonyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 594.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-ethanesulfonyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 580.4 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethanesulfonyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 580.5 (M+H);-   4-(1,1-Difluoro-propyl)-1-(2-fluoro-benzyl)-6-[5-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 558.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-ethylsulfanyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 548.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(2-methanesulfonyl-6-trifluoromethyl-pyridin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 620.3 (M+H);-   Acetic acid    1-(5-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-2-yl}-2-methanesulfonyl-pyridin-3-yl)-ethyl    ester, MS (ES+): 638.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(2-ethanesulfonyl-6-ethyl-pyridin-4-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 594.2 (M+H);-   1-(4-Chloro-benzyl)-6-[5-(6-methanesulfonyl-5-methyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 564 (M+H);-   1-(2,4-Difluoro-benzyl)-6-{5-[5-(1-hydroxy-ethyl)-6-methanesulfonyl-pyridin-3-yl]-thiophen-2-yl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 596.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(6-morpholin-4-yl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-[5-(2-Chloro-pyridin-4-yl)-thiophen-2-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 508.1 (M+H);-   1-(4-Chloro-benzyl)-6-[5-(3-ethanesulfonyl-phenyl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 563.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[5-(6-piperazin-1-yl-pyridin-3-yl)-thiophen-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 558.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-[4-(6-piperazin-1-yl-pyridin-3-yl)-thiophen-2-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 558.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(6-morpholin-4-yl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 559.3 (M+H);-   6-(4-Benzo[1,3]dioxol-5-yl-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   6-(5-Benzo[1,3]dioxol-5-yl-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 516.7 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 531.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[5-(2,3-dihydro-benzofuran-5-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 515.3 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[4-(2,3-dihydro-benzofuran-5-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;-   1-(2,4-Dichloro-benzyl)-6-[5-(4-methyl-naphthalen-1-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,-   1-(2,4-Difluoro-benzyl)-6-(5-naphthalen-2-yl-thiophen-2-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 523.2 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(5-naphthalen-1-yl-thiophen-2-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 523.3 (M+H);-   6-(1-Benzyl-1H-pyrazol-4-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 471.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(1-phenyl-1H-pyrazol-4-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 456.8 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 485.2 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-6-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 525.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 471.2 (M+H);-   1-(2,4-Dichloro-benzyl)-6-[1-benzyl-1H-pyrazol-4-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;-   1-(2,4-Difluoro-benzyl)-6-[1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 501.3 (M+H);-   6-[1-(3-Cyano-4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 550.1 (M+H);-   6-[1-(3-Chloro-4-cyano-phenyl)-1H-pyrazol-4-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 516.1 (M+H);-   6-[1-(3-Chloro-4-ethoxy-phenyl)-1H-pyrazol-4-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 535.1 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[1-(4-methanesulfonyl-phenyl)-1H-pyrazol-4-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 535 (M+H);-   1-(2,4-Difluoro-benzyl)-6-[1-(3,4-dimethoxy-phenyl)-1H-pyrazol-4-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 517.1 (M+H);-   6-[1-(4-Cyano-3-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 550.3 (M+H);-   1-(2,4-Difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[1-(6-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 526.3 (M+H); and-   1-(2,4-Difluoro-benzyl)-2-oxo-4-trifluoromethyl-6-[1-(5-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-1,2-dihydro-pyridine-3-carbonitrile,    MS (ES+): 526.3 (M+H).

Example 7 FRET Coactivator Assay

The FRET coactivator assay measures the ability of LXR ligands topromote protein-protein interactions between the ligand binding domain(LBD) of LXR and transcriptional coactivator proteins. The assayinvolves the use a recombinant Glutathione-S-transferase (GST)-nuclearreceptor ligand binding domain (LBD) fusion protein and a syntheticbiotinylated peptide sequence derived from the receptor interactingdomain of a co-activator peptide such as the steroid receptorcoactivator 1 (SRC-1). Typically GST-LBD is labeled with a europiumchelate (donor) via a europium-tagged anti-GST antibody, and thecoactivator peptide is labeled with allophycocyanin via astreptavidin-biotin linkage.

In the presence of an agonist for the nuclear receptor, the peptide isrecruited to the GST-LBD bringing europium and allophycocyanin intoclose proximity to enable energy transfer from the europium chelate tothe allophycocyanin. Upon excitation of the complex with light at 340 nmexcitation energy absorbed by the europium chelate is transmitted to theallophycocyanin moiety resulting in emission at 665 nm. If the europiumchelate is not brought into close proximity to the allophycocyaninmoiety there is little or no energy transfer and excitation of theeuropium chelate results in emission at 615 nm. Thus the intensity oflight emitted at 665 nm gives an indication of the strength of theprotein-protein interaction.

Required Materials:

1. Partially purified recombinant protein comprisingglutathione-S-transferase fused in frame to the LXR-ligand bindingdomain (comprising amino acids 188-447 of human LXRα, or amino acids198-461 of human LXRβ).

2. Biotinylated peptide containing a SRC-1 LXXLL receptor interactionmotif (B-SRC-1)

3. Anti-GST antibody conjugated to an Europium chelate (αGST-K) (FromWallac/PE Life Sciences Cat# AD0064)

4. Streptavidin linked allophycocyanin (SA-APC) (From Wallac/PE LifeSciences CAT# AD0059A)

5. 1×FRET Buffer: (20 mM KH₂PO₄/K₂HPO₄ pH 7.3, 150 mM NaCl, 2.5 mMCHAPS, 2 mM EDTA, 1 mM DTT (add fresh))

6. 96 well or 384 well black multiwell plates (from LJL)

Stock Solutions:

0.5 M KH₂PO₄/K₂HPO₄: pH 7.3

5 M NaCl

80 mM (5%) CHAPS

0.5 M EDTA pH 8.0

1 M DTT (keep at −20° C.)

Preparation of Screening Reagents:

Prepare reaction mixture for the appropriate number of wells bycombining the following reagents 5 nM/well GST-hLXRαLBD, 5 nM/wellGST-hLXRβLBD, 5 nM/well Anti-GST antibody (Eu), 12 nM/well biotin-SRC-1peptide, 12 nM/well APC-SA adjust the volume to 10 μL/well with 1×-FRETbuffer.

Procedure:

Add 0.5 μL of a 1 mM stock compound (for approx. 10 μM finalconcentration) or solvent to each well in a 96 well or 384 well blackplate (LJL).

Add 10 μl reaction mixture (prepared above) to each well of themultiwell plate.

Incubate covered or in the dark (the APC is light sensitive) at ambienttemperature for 1-4 hours. After this time if reactions are not readthey can be stored at 4° C. for several more hours without too much lossof signal.

Read the plate using an LJL Analyst, or similar instrument, using thefollowing conditions:

Channel 1: Excitation is 330 nm and emission is 615. This is for Euchelate

Channel 2: Excitation is 330 nm and emission is 665. This is for APC

For channel 1: Flashes per well=100; Integration time=1000 μs; intervalbetween flashes=1×10 ms; Delay after flash=200 μs

For channel 2: Flashes per well=100; Integration time=100 μs; intervalbetween flashes=1×10 ms; Delay after flashes=65 μs

Example 8 Scintillation Proximity Assay (SPA)

The SPA assay measures the radioactive signal generated by the bindingof ³H-24,25-epoxycholesterol to LXRα or LXRβ. The basis of the assay isthe use of SPA beads containing a scintillant, such that when binding tothe receptor brings the labeled ligand into proximity with the bead, theenergy from the label stimulates the scintillant to emit light. Thelight is measured using a standard microplate scintillation reader. Theability of a ligand to bind to a receptor can be measured by assessingthe degree to which the compound can compete off a radiolabelled ligandwith known affinity for the receptor.

Required Materials:

1. Label: ³H-24,25-epoxy-cholesterol (Amersham)

2. LXRα lysate: Baculovirus expressed LXRα/RXR heterodimer with RXRhaving a 6-HIS tag produced as a crude lysate

3. LXRβ lysate: Baculovirus expressed LXR/RXR heterodimer with RXRhaving a 6-HIS tag produced as a crude lysate

4. SPA beads: Ysi copper His-tag SPA beads (Amersham)

5. Plates: Non-binding surface 96-well plate (Corning)

6. Protein lysate dilution buffer: (20 mM Tris-HCl pH 7.9, 500 mM NaCl,5 mM Imidazole).

7. 2×SPA Buffer: (40 mM K₂HPO₄/KH₂PO₄ pH 7.3, 100 mM NaCl, 0.05% Tween20, 20% Glycerol, 4 mM EDTA)

8. 2×SPA Buffer w/o EDTA: (40 mM K₂HPO₄/KH₂PO₄ pH 7.3, 100 mM NaCl,0.05% Tween 20, 20% Glycerol)

Stock Solutions

0.5 M K₂HPO₄/KH₂PO₄ pH 7.3

0.5 M EDTA pH 8.0

5 M NaCl

10% Tween-20

Glycerol

Preparation of Protein Lysates

Baculovirus expression plasmids for human RXR α (accession NoNM_(—)002957), LXRα (accession No U22662), LXRβ (accession No U07132)were made by cloning the appropriate full-length cDNAs into thepBacPakhis1 vector (Clontech, CA) following standard procedures.Insertion of the cDNAs into the pBAcPakhis1 vector polylinker created anin frame fusion to the cDNA to an N-terminal poly-His tag present inpBacPakhis1. Correct cloning was confirmed by restriction mapping,and/or sequencing.

Cell lysates were prepared by infecting healthy, Sf9 insect cells at adensity of approximately 1.25×10⁶/ml at 27° C., in a total volume of 500mL per 1 L sized spinner flasks, cultured under standard conditions. Toprepare LXRα lysate, insect cells were co-transfected with the LXRαexpression cassette at an M.O.I of 0.5 to 0.8 and with the RXRexpression cassette at a M.O.I. of approximately 1.6. To prepare LXRβlysate, insect cells were co-transfected with the LXRβ expressioncassette at an M.O.I of approximately 1.6 and with the RXR expressioncassette at a M.O.I. of approximately 1.6. In both cases cells wereincubated for 48 hours at 27° C. with constant shaking prior toharvesting.

After incubation, cells were harvested by centrifugation and pelleted.Cell pellets were resuspended in two volumes of ice-cold freshlyprepared extraction buffer (20 mM Tris pH 8.0, 10 mM Imidazole, 400 mMNaCl, containing one EDTA free protease inhibitor tablet (Roche CatalogNo: 1836170) per 10 ml of extraction buffer).

Cells were homogenized slowly on ice using a Douncer to achieve 80-90%cell lysis. The homogenate was centrifuged in a pre-chilled rotor (Ti50or Ti70, or equivalent) at 45,000 rpm for 30 minutes at 4° C. Aliquotsof the supernatant were frozen on dry ice and stored frozen at −80° C.until quantification and quality control. Aliquots of the lysates weretested in the SPA assay to ensure lot to lot consistency, and viaSDS-PAGE analysis after purification using Ni-NTA Resin (Qiagen) andadjusted for protein concentration and expression level prior to use inscreening assays.

Preparation of Screening Reagents

[³H] 24,25 Epoxycholesterol (EC) solution: For a single 384-well plate(or 400 wells), 21 μL of [³H] EC (specific activity 76.5 Ci/mmol,concentration 3.2 mCi/mL) was added to 4.4 mL of 2×SPA buffer to providefor a final concentration of 200 nM. For each additional 384-well plate,an additional 19.1 μL of [³H] EC was added to 4.0 mL of additional 2×SPAbuffer. The final concentration of [³H] EC in the well was 50 nM.

LXRα lysate (prepared as above) was diluted with protein lysate dilutionbuffer. 1400 μL of diluted LXRα lysate was prepared per 384-well plate,(or 200 wells) and 1120 μL of diluted LXRα lysate was prepared for eachadditional 384-well plate.

LXRβ lysate (prepared as above) was diluted with protein lysate dilutionbuffer. 1400 μL of diluted LXRβ lysate was prepared per 384-well plate,(or 200 wells) and 1120 μL of diluted LXRβ lysate was prepared for eachadditional 384-well plate.

SPA bead solution: For a 384-well plate (or 400 wells), 3.75 mL of 2×SPAbuffer w/o EDTA, 2.25 mL of H₂O, and 1.5 mL of Ysi His-tag SPA beads(vortex well before taking) were mixed together. For each additional384-well plate, an additional 3.5 mL of 2×SPA buffer w/o EDTA, 2.1 mL ofH₂O, and 1.4 mL of Ysi His-tag SPA beads were mixed together.

Procedure:

Appropriate dilutions of each compound were prepared and pipetted intothe appropriate wells of a multiwell plate.

9.1 μL of [³H] EC was added to each well of column 2-23 of the multiwellplate.

5 μl of diluted LXRα lysate was added to each well of column 2-23 on oddrows of the multiwell plate.

5 μL of diluted LXRβ lysate was added to each well of column 2-23 oneven rows of the multiwell plate.

17.5 μL of SPA bead solution was added to each well of column 2-23 ofthe multiwell plate.

The plates were covered with clear sealer and placed in an incubator atambient temperature for 1 hour.

After incubation plates were analyzed using a luminescent plate reader(MicroBeta, Wallac) using the program n ABASE 3H_(—)384DPM. The settingfor n ABASE 3H_(—)384DPM was:

Counting Mode: DPM

Sample Type: SPA

ParaLux Mode: low background

Count time: 30 sec.

Assays for LXRα and LXRβ were performed in the identical manner. Thedetermined Ki represents the average of at least two independent doseresponse experiments. The binding affinity for each compound may bedetermined by non-linear regression analysis using the one sitecompetition formula to determine the IC₅₀ where:

$Y = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{\left( {1 + 10^{{X\text{-}\log\;{IC}\; 50}\;}} \right)}}$The Ki is than calculated using the Cheng and Prusoff equation where:Ki=IC ₅₀/(1+[Concentration of Ligand]/Kd of Ligand)For this assay, typically the Concentration of Ligand=50 nM and the Kdof EC for the receptor is 200 nM as determined by saturation binding.

The compounds of the invention demonstrated the ability to bind to LXRαand/or LXRβ when tested in this assay.

Example 15 Co-Transfection Assay

To measure the ability of compounds to activate or inhibit thetranscriptional activity of LXR in a cell based assay, theco-transfection assay was used. It has been shown that LXR functions asa heterodimer with RXR. For the co-transfection assay, expressionplasmids for LXR and RXR are introduced via transient transfection intomammalian cells along with a luciferase reporter plasmid that containsone copy of a DNA sequence that is bound by LXR-RXR heterodimers (LXRE;Willy, P. et al. 1995). Treatment of transfected cells with an LXRagonist increases the transcriptional activity of LXR, which is measuredby an increase in luciferase activity. Similarly, LXR antagonistactivity can be measured by determining the ability of a compound tocompetitively inhibit the activity of a LXR agonist.

Required Materials

1. CV-1 African Green Monkey Kidney Cells

2. Co-transfection expression plasmids, comprising full-length LXRα(pCMX-hLXR α), LXRβ (pCMX-hLXR β), or RXRα (pCMX-RXR), reporter plasmid(LXREx1-Tk-Luciferase), and control (pCMX-Galactosidase expressionvector) (Willey et al. Genes & Development 9 1033-1045 (1995)).

3. Transfection reagent such as FuGENE6 (Roche).

4. 1× Cell lysis buffer (1% Triton X 100 (JT Baker X200-07), 10%Glycerol (JT Baker M778-07), 5 mM Ditriotreitol (Quantum Bioprobe DTT03;add fresh before lysing), 1 mM EGTA (Ethylene Glycol-bis(B-Amino ethylether)-N,N,N′,N′-Tetracetic Acid) (Sigma E-4378), 25 mM Tricine (ICN807420) pH 7.8)

5. 1× Luciferase assay buffer (pH at 7.8) (0.73 mM ATP, 22.3 mM Tricine,0.11 mM EDTA, 33.3 mM DTT)

6. 1× Luciferrin/CoA (11 mM Luciferin, 3.05 mM Coenzyme A, 10 mM HEPES)

Preparation of Screening Reagents

CV-1 cells were prepared 24 hours prior to the experiment by platingthem into T-175 flasks or 500 cm² dishes in order to achieve 70-80%confluency on the day of the transfection. The number of cells to betransfected was determined by the number of plates to be screened. Each384 well plate requires 1.92×106 cells or 5000 cells per well. DNATransfection Reagent was prepared by mixing the required plasmid DNAswith a cationic lipid transfection reagent FuGENE6 (Roche) by followingthe instructions provided with the reagents. Optimal DNA amounts weredetermined empirically per cell line and size of vessel to betransfected. 10-12 mL of media was added to the DNA Transfection Reagentand this mixture was added to the cells after aspirating media from theT175 cm² flask. Cells were then incubated at least 5 hours at 37° C. toprepare screening cells.

Luciferase assay reagent was prepared by combining before use (per 10mL):

10 mL 1× Luciferase assay buffer

0.54 mL of 1× Luciferrin/CoA

0.54 mL of 0.2 M Magnesium sulfate

Procedure

Assay plates were prepared by dispensing 5 μL of compound per well of a384 well plate to achieve final compound concentration of 10 μM and nomore than 1% DMSO. Media was removed from the screening cells, the cellstrypsinized, harvested cells by centrifugation, counted, and plated at adensity of approximately 5000 cells per well in the 384 well assay plateprepared above in a volume of about 45 μL. Assay plates containing bothcompounds and screening cells (50 μL in total volume) were incubated for20 hours at 37° C.

After incubation with compounds, media was removed from the cells andlysis buffer (30 μL/well) added. After 30 minutes at ambienttemperature, luciferase assay buffer (30 μL/well) was added and theassay plates read on a luminometer (PE Biosystems Northstar reader withon-board injectors, or equivalent). Plates were read immediately afteraddition of luciferase assay buffer.

The LXR/LXRE co-transfection assay can be used to establish theEC₅₀/IC₅₀ values for potency and percent activity or inhibition forefficacy. Efficacy defines the activity of a compound relative to a highcontrol((N-(3-((4-fluorophenyl)-(naphthalene-2-sulfonyl)amino)propyl)-2,2-dimethylpropionamide))or a low control (DMSO/vehicle). The dose response curves are generatedfrom an 8 point curve with concentrations differing by ½ LOG units. Eachpoint represents the average of 4 wells of data from a 384 well plate.

The data from this assay is fitted to the following equation, from theEC₅₀ value may be solved:Y=Bottom+(Top−Bottom)/(1+10^(((logEC50-X)*HillSlope)))

The EC₅₀/IC₅₀ is therefore defined as the concentration at which anagonist or antagonist elicits a response that is half way between theTop (maximum) and Bottom (baseline) values. The EC₅₀/IC₅₀ valuesrepresented are the averages of at least 3 independent experiments. Thedetermination of the relative efficacy or % control for an agonist is bycomparison to the maximum response achieved by((N-(3-((4-fluorophenyl)-(naphthalene-2-sulfonyl)-amino)propyl)-2,2-dimethylpropionamide)that is measured individually in each dose response experiment.

For the antagonist assay, a LXR agonist can be added to each well of a384 well plate to elicit a response. The % inhibition for eachantagonist is therefore a measurement of the inhibition of the activityof the agonist. In this example, 100% inhibition would indicate that theactivity of a specific concentration of LXR agonist has been reduced tobaseline levels, defined as the activity of the assay in the presence ofDMSO only.

Compounds of the invention, when tested in this assay, demonstrated theability to modulate the activity of LXRα and/or LXRβ.

Example 16 In Vivo Studies

In order to evaluate direct regulation of key target genes by thecompounds of the invention, animals are administered a single oral doseof the test compound and tissues collected at six or fifteen hours afterdose. Male C57BL/6 mice (n=8) are dosed by oral gavage with vehicle orcompound. At six and fifteen hours after the dose, animals are bled viathe retro orbital sinus for plasma collection. Animals are theneuthanized and tissues, such as liver and intestinal mucosa arecollected and snap frozen for further analysis. Plasma is analyzed for alipid parameters, such as total cholesterol, HDL cholesterol andtriglyceride levels. RNA is extracted for frozen tissues and can beanalyzed by quantitative real time PCR for regulation of key targetgenes. To identify specificity of target gene regulation by LXRsubtypes, LXR deficient mice (LXRα−/− or LXRβ−/−) and C57BL/6 wild-typecontrols are used in this same protocol.

Plasma Lipid Evaluation:

To compare the effects of compounds on plasma cholesterol andtriglycerides, animals are dosed with compound for one week and plasmalipid levels are monitored throughout the study. Male C57BL/6 mice (n=8)are dosed daily by oral gavage with vehicle or compound. Plasma samplesare taken on day −1 (in order to group animals), day 1, 3, and 7.Samples are collected three hours after the daily dose. On day 7 of thestudy, following plasma collection, animals are euthanized and tissues,such as liver and intestinal mucosa are collected and snap frozen forfurther analysis. Plasma is analyzed for lipid parameters, such as totalcholesterol, HDL cholesterol and triglyceride levels. RNA is extractedfor frozen tissues and can be analyzed by quantitative real time PCR forregulation of key target genes. To identify specificity of target generegulation by LXR subtypes, LXR deficient mice (LXRα−/− or LXRβ−/−) andC57BL/6 wild-type controls are used in this same protocol.

Cholesterol Absorption:

Evaluation of compounds to inhibit cholesterol absorption is done viameasurement of labeled cholesterol in feces. Male A129 mice (n=7) aredosed daily by oral gavage with vehicle or compound for 7 days. On day 7of the study, animals are administered [¹⁴C]-cholesterol and[³H]-sitostanol by oral gavage. Animals are individually housed on wireracks for the next 24 hours in order to collect feces. Feces are thendried and ground to a fine powder. Labeled cholesterol and sitostanolare extracted from the feces and ratios of the two are counted on aliquid scintillation counter in order to evaluate the amount ofcholesterol absorbed by the individual animal.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet, are incorporated herein by reference, intheir entirety.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A compound having the following formula (II):

wherein: n is 0 to 4; m is 0 to 5; R¹ is hydrogen, aralkyl orheteroarylalkyl; R² is hydrogen, cyano or —R⁷—N(R⁸)₂; R³ is haloalkyl;each R⁴ is independently halo, alkyl or haloalkyl; each R⁵ isindependently selected from the group consisting of halo, nitro, alkyl,alkenyl, aryl, aralkyl, aralkenyl, haloalkyl, haloalkenyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl, —R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸, —R⁷—O—R⁹—C(O)OR⁸,—R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—C(O)N(R⁸)OR⁸,—R⁷—C(O)N(R⁸)N(R⁸)₂, —R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸, —R⁷—C(S)N(R⁸)₂,—R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—S(O)_(t)R⁸ (where t is 0 to 2) and—R⁷—S(O)₂N(R⁸)₂; R⁶ is —OR⁷—, a direct bond, a straight or branchedalkylene chain, a straight or branched alkenylene chain or a straight orbranched alkynylene chain; each R⁷ is independently selected from adirect bond, a straight or branched alkylene chain or a straight orbranched alkenylene chain; each R⁸ is independently selected fromhydrogen, alkyl, alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl,aralkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R⁹ is independently selected from astraight or branched alkylene chain or a straight or branched alkenylenechain; R¹⁰ is alkyl, aryl, aralkyl or cycloalkylalkyl; and R¹¹ ishydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heterarylalkyl; as astereoisomer, a mixture of stereoisomers, a racemic mixture ofstereoisomers, or as a tautomer; or as a pharmaceutically acceptablesalt thereof.
 2. The compound of claim 1 wherein: n is 0 or 1; m is 0 to2; R¹ is aralkyl or heteroarylalkyl; R² is cyano; R³ is haloalkyl; R⁴ ishalo, alkyl or haloalkyl; each R⁵ is independently selected from thegroup consisting of halo, nitro, alkyl, alkenyl, haloalkyl,heterocyclyl, heteroaryl, —R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸, —R⁷—O—R⁹—C(O)OR⁸,—R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—C(O)N(R⁸)OR⁸,—R⁷—C(O)N(R⁸)N(R⁸)₂, —R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸, —R⁷—C(S)N(R⁸)₂,—R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—S(O)_(t)R⁸ (where t is 0 to 2) and—R⁷—S(O)₂N(R⁸)₂; R⁶ is —OR⁷—, a direct bond, a straight or branchedalkenylene chain or a straight or branched alkynylene chain; each R⁷ isindependently selected from a direct bond or a straight or branchedalkylene chain; each R⁸ is independently selected from hydrogen, alkyl,alkenyl, haloalkyl, haloalkenyl, aryl, aralkyl, aralkenyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; each R⁹ is a straight or branched alkylene chainoptionally substituted by aryl or heteroaryl; R¹⁰ is alkyl, aryl,aralkyl or cycloalkylalkyl; and R¹¹ is hydrogen, alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylor heterarylalkyl.
 3. The compound of claim 2 wherein R⁶ is —OR⁷—. 4.The compound of claim 3 wherein R¹ is aralkyl optionally substitutedwith one or more substituents independently selected from alkyl, halo orhaloalkyl.
 5. The compound of claim 4 wherein n is 0 or 1; m is 0 to 2;R² is cyano; R³ is trifluoromethyl; R⁴ is methyl, 1-methylethyl orchloro; each R⁵ is independently selected from the group consisting ofhalo, alkyl, alkenyl or haloalkyl.
 6. The compound of claim 5 whereineach R⁵ is independently selected from chloro, bromo, fluoro, methyl,ethyl, 1-methylethyl, 1,1-dimethylethyl, ethenyl or trifluoromethyl. 7.The compound of claim 6 selected from the group consisting of thefollowing:1-(2,4-Dimethyl-benzyl)-6-[4-(3-isopropyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(4-tert-Butyl-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(4-fluoro-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(2,4-dimethyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(2,5-dimethyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(2,6-dimethyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(2-Chloro-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(3-Chloro-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[3-methyl-4-(2-trifluoromethyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[3-methyl-4-(3-trifluoromethyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(3-Bromo-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(4-Bromo-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(3-Benzyloxy-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(2,4-dimethyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(4-Benzyloxy-phenyl)-1-(2,4-dichloro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dichloro-benzyl)-2-oxo-6-(4-phenoxy-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-(4-phenoxy-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2-Chloro-4-fluoro-benzyl)-2-oxo-6-(4-phenoxy-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(4-Benzyloxy-phenyl)-1-(2-chloro-4-fluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dichloro-benzyl)-2-oxo-4-pentafluoroethyl-6-(4-phenoxy-phenyl)-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-(3-isopropyl-4-phenoxy-phenyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-(3-isopropyl-4-o-tolyloxy-phenyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(2-ethyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(2,5-dimethyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(2,4-dimethyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(3,4-dimethyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-(3-isopropyl-4-m-tolyloxy-phenyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[3-isopropyl-4-(3-isopropyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[3-isopropyl-4-(4-isopropyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-(3-isopropyl-4-p-tolyloxy-phenyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(4-tert-Butyl-phenoxy)-3-isopropyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[3-isopropyl-4-(4-vinyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(4-ethyl-2-methyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(4-ethyl-2-methyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(2-ethyl-4-methyl-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(2-ethyl-4-methyl-phenoxy)-3-isopropyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(4-Benzyloxy-3-chloro-phenyl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[3-Chloro-4-(4-fluoro-phenoxy)-phenyl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;and1-(2,4-Difluoro-benzyl)-6-[4-(4-fluoro-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,or a pharmaceutically acceptable salt of any of the foregoing.
 8. Thecompound of claim 4 wherein: n is 0 or 1; m is 1 or 2; R² is cyano; R³is trifluoromethyl; R⁴ is methyl, 1-methylethyl or chloro; each R⁵ isindependently selected from the group consisting of haloalkyl, —R⁷—CN,—R⁷—N(R⁸)₂, —R⁷—OR⁸ and R⁷—O—R⁹—C(O)OR⁸ each R⁷ is independentlyselected from a direct bond or methylene chain; each R⁸ is independentlyselected from hydrogen, alkyl, aryl and aralkyl; and R⁹ is a methylenechain.
 9. The compound of claim 8 selected from the group consisting ofthe following:6-[4-(4-Dimethylamino-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(4-methoxy-phenoxy)-3-methyl-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(3-Cyano-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(4-Benzyloxy-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(3-Benzyloxy-phenoxy)-3-methyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(3-Cyano-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(4-Cyano-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(4-Dimethylamino-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(4-hydroxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(3-hydroxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(4-hexyloxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-{4-[4-(3-methyl-butoxy)-phenoxy]-phenyl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(3-hexyloxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-{4-[3-(3-methyl-butoxy)-phenoxy]-phenyl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-phenoxy)-aceticacid benzyl ester;(4-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-phenoxy)-aceticacid benzyl ester;1-(2,4-Dimethyl-benzyl)-2-oxo-6-[4-(4-phenylamino-phenoxy)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(4-Benzylamino-phenoxy)-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-[4-(3-hydroxymethyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(3-Benzyloxy-phenoxy)-3-isopropyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[4-(4-Benzyloxy-phenoxy)-3-isopropyl-phenyl]-1-(2,4-dimethyl-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-[4-(3-hydroxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-[4-(4-hydroxy-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;and6-[4-(3-Cyano-4-trifluoromethyl-phenoxy)-phenyl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,or a pharmaceutically acceptable salt of any of the foregoing.
 10. Thecompound of claim 4 wherein: n is 0 or 1; m is 1 or 2; R² is cyano; R³is trifluoromethyl; R⁴ is methyl, 1-methylethyl or chloro; each R⁵ isindependently selected from the group consisting of heteroaryl, —R⁷—OR⁸,—R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—C(O)N(R⁸)OR⁸,—R⁷—C(O)N(R⁸)N(R⁸)₂, —R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸, —R⁷—C(S)N(R⁸)₂ and—R⁷—S(O)_(t)R⁸ (where t is 0 to 2); each R⁷ is independently selectedfrom a direct bond or a straight or branched alkylene chain; each R⁸ isindependently selected from hydrogen, alkyl, haloalkyl, aryl, aralkyl,aralkenyl, cycloalkyl or heterocyclyl optionally substituted withhydroxy; R⁹ is a straight or branched alkylene chain (optionallysubstituted by phenyl or imidazolyl); and R¹¹ is hydrogen, alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heterarylalkyl.
 11. The compound of claim 10 wherein: m is1 or 2; each R⁵ is independently selected from —R⁷—OR⁸, —R⁷—C(O)R¹¹,—R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—C(O)N(R⁸)OR⁸ or —R⁷—C(O)N(R⁸)N(R⁸)₂;each R⁷ is independently selected from a direct bond or methylene; eachR⁸ is independently selected from hydrogen, methyl, ethyl,1,1-dimethylethyl, benzyl, 2-phenylethyl, cyclohexyl or piperidinyloptionally substituted by hydroxy; and R¹¹ is hydrogen, alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heterarylalkyl.
 12. The compound of claim 11 selected fromthe group consisting of the following:4-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-2-methyl-phenoxy}-benzoicacid methyl ester;3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-2-methyl-phenoxy}-benzoicacid methyl ester;4-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoicacid;3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N-methyl-benzamide;3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-benzamide;1-(2,4-Dimethyl-benzyl)-2-oxo-6-{4-[3-(piperidine-1-carbonyl)-phenoxy]-phenyl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-{4-[3-(3-hydroxy-piperidine-1-carbonyl)-phenoxy]-phenyl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;N-Benzyl-3-{4-[5-cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzamide;3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoicacid N′-phenyl-hydrazide;3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N-cyclopentyl-benzamide;3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N-methoxy-N-methyl-benzamide;3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N—((S)-1-phenyl-ethyl)-benzamide;3-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-benzamide;3-Benzyloxy-5-{4-[5-cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoicacid methyl ester;3-Benzyloxy-5-{4-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-benzamide;3-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-5-hydroxy-N,N-dimethyl-benzamide;2-Benzyloxy-5-{4-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-benzamide;5-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-2-hydroxy-N,N-dimethyl-benzamide;3-{4-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N-methyl-benzamide;N-tert-Butyl-3-{4-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzamide;and1-(2,4-Difluoro-benzyl)-2-oxo-6-{4-[3-(piperidine-1-carbonyl)-phenoxy]-phenyl}-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,or a pharmaceutically acceptable salt of any of the foregoing.
 13. Thecompound of claim 4 wherein: n is 0 or 1; m is 1 or 2; R² is cyano; R³is trifluoromethyl; R⁴ is methyl, 1-methylethyl or chloro; each R⁵ isindependently selected from the group consisting of heteroaryl,—R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸, —R⁷—C(S)N(R⁸)₂ and —R⁷—S(O)_(t)R⁸ (where t is0 to 2); each R⁷ is independently selected from a direct bond or astraight or branched alkylene chain; each R⁸ is independently selectedfrom hydrogen or alkyl, haloalkyl, aryl, aralkyl, aralkenyl, cycloalkylor heterocyclyl; and R⁹ is a straight or branched alkylene chain(optionally substituted by phenyl or imidazolyl).
 14. The compound ofclaim 13 wherein: n is 0 or 1; m is 1; R² is cyano; R³ istrifluoromethyl; R⁴ is chloro; R⁵ is —R⁷—C(O)N(R⁸)—R⁹—C(O)OR⁸; R⁷ is adirect bond; each R⁸ is independently hydrogen or alkyl; and R⁹ is astraight or branched alkylene chain optionally substituted by phenyl orimidazolyl.
 15. The compound of claim 14 selected from the groupconsisting of the following:(S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-propionicacid methyl ester;(R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-propionicacid methyl ester;(S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-methyl-butyricacid methyl ester;(R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-methyl-butyricacid methyl ester;(S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-4-methyl-pentanoicacid methyl ester;(R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-4-methyl-pentanoicacid methyl ester;(S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-phenyl-propionicacid methyl ester;(R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-phenyl-propionicacid methyl ester;(S)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-(1H-imidazol-4-yl)-propionicacid methyl ester;(R)-2-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-3-(1H-imidazol-4-yl)-propionicacid methyl ester;(S)-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-phenyl-aceticacid methyl ester; and(R)-(3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-benzoylamino)-phenyl-aceticacid methyl ester, or a pharmaceutically acceptable salt of any of theforegoing.
 16. The compound of claim 13 wherein: n is 0 or 1; m is 1; R²is cyano; R³ is trifluoromethyl; R⁴ is methyl, 1-methylethyl or chloro;each R⁵ is independently selected from the group consisting ofphthalimidyl, —R⁷—C(S)N(R⁸)₂ and —R⁷—S(O)_(t)R⁸ (where t is 0 or 2);each R⁷ is a direct bond; and each R⁸ is independently selected fromhydrogen or alkyl.
 17. The compound of claim 16 selected from the groupconsisting of the following:1-(2,4-Dimethyl-benzyl)-6-[4-(4-methylsulfanyl-phenoxy)-phenyl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Dimethyl-benzyl)-6-{4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-phenyl}-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;3-{4-[5-Cyano-1-(2,4-dimethyl-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-phenoxy}-N,N-dimethyl-thiobenzamide;and6-[3-Chloro-4-(4-methanesulfonyl-phenoxy)-phenyl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,or a pharmaceutically acceptable salt of any of the foregoing.
 18. Thecompound of claim 3 wherein R¹ is heteroarylalkyl.
 19. The compound ofclaim 18 wherein: n is 0 or 1; m is 0-2; R¹ is optionally substitutedthiazol-5-ylmethyl; R² is cyano; R³ is trifluoromethyl; R⁴ is methyl,1-methylethyl or chloro; each R⁵ is independently selected from thegroup consisting of halo, alkyl, alkenyl or haloalkyl.
 20. The compoundof claim 19, i.e., namely1-(2,5-Diethyl-thiazol-4-ylmethyl)-2-oxo-6-(4-phenoxy-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,or a pharmaceutically acceptable salt thereof.
 21. The compound of claim2 wherein: R¹ is aralkyl optionally substituted with one or moresubstituents independently selected from alkyl, halo or haloalkyl; eachR⁵ is independently selected from the group consisting of halo, nitro,alkyl, alkenyl, haloalkyl, —R⁷—CN, —R⁷—N(R⁸)₂, —R⁷—OR⁸, —R⁷—C(O)R¹¹,—R⁷—C(O)OR⁸, —R⁷—C(O)N(R⁸)₂, —R⁷—N(R⁸)C(O)OR¹⁰, —R⁷—S(O)_(t)R⁸ (where tis 0 to 2) and —R⁷—S(O)₂N(R⁸)₂; R⁶ is a direct bond, a straight orbranched alkenylene chain or a straight or branched alkynylene chain;each R⁷ is independently selected from a direct bond or a straight orbranched alkylene chain; each R⁸ is independently selected fromhydrogen, alkyl, cycloalkyl, cycloalkylalkyl or heterocyclyl; each R⁹ isa straight or branched alkylene chain optionally substituted by aryl orheteroaryl; R¹⁰ is alkyl, aryl, aralkyl or cycloalkylalkyl; and R¹¹ ishydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heterarylalkyl.
 22. Thecompound of claim 21 wherein: n is 0; m is 1 or 2; R¹ is benzyloptionally substituted with one or more substituents independentlyselected from alkyl, halo or haloalkyl; R² is cyano; R³ istrifluoromethyl; each R⁵ is independently selected from the groupconsisting of alkyl, trifluoromethyl, —R⁷—OR⁸ and R⁷—S(O)_(t)R⁸ (where tis 0 to 2); R⁶ is a direct bond; R⁷ is a direct bond; R⁸ is hydrogen oralkyl; and R⁹ is a straight or branched alkylene chain.
 23. The compoundof claim 22 selected from the group consisting of the following:1-(2,4-Difluoro-benzyl)-6-(4′-methanesulfonyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(4′-methanesulfonyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(4′-ethylsulfanyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(4′-ethanesulfonyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(4′-methylsulfanyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(5′-methylsulfanyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(4′-methylsulfanyl-3′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(5′-methylsulfanyl-3′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(4′-methanesulfonyl-3′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(4′-methanesulfonyl-3′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(3′-methanesulfonyl-5′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(3′-ethanesulfonyl-5′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-2-sulfonyl)-5′-trifluoromethyl-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(4′-ethoxy-3′-methanesulfonyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-[5′-(propane-1-sulfinyl)-3′-trifluoromethyl-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[5′-(Butane-1-sulfinyl)-3′-trifluoromethyl-biphenyl-3-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-(5′-phenylmethanesulfinyl-3′-trifluoromethyl-biphenyl-3-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(5′-Cyclopropylmethanesulfinyl-3′-trifluoromethyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-[5′-(propane-1-sulfinyl)-3′-trifluoromethyl-biphenyl-4-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[5′-(Butane-1-sulfinyl)-3′-trifluoromethyl-biphenyl-4-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-(5′-phenylmethanesulfinyl-3′-trifluoromethyl-biphenyl-4-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(5′-Cyclopropylmethanesulfinyl-3′-trifluoromethyl-biphenyl-4-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(5′-ethanesulfinyl-3′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-2-sulfinyl)-5′-trifluoromethyl-biphenyl-4-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-1-sulfonyl)-5′-trifluoromethyl-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-1-sulfonyl)-5′-trifluoromethyl-biphenyl-4-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[3′-(Butane-1-sulfonyl)-5′-trifluoromethyl-biphenyl-3-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-[3′-(Butane-1-sulfonyl)-5′-trifluoromethyl-biphenyl-4-yl]-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-(3′-phenylmethanesulfonyl-5′-trifluoromethyl-biphenyl-3-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-(3′-phenylmethanesulfonyl-5′-trifluoromethyl-biphenyl-4-yl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(3′-Cyclopropylmethanesulfonyl-5′-trifluoromethyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(3′-Cyclopropylmethanesulfonyl-5′-trifluoromethyl-biphenyl-4-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(3′-ethanesulfonyl-5′-trifluoromethyl-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(propane-2-sulfonyl)-5′-trifluoromethyl-biphenyl-4-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(5′-isopropyl-3′-methanesulfonyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(5′-ethyl-3′-methanesulfonyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(3′-ethanesulfonyl-5′-isopropyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;and1-(2,4-Difluoro-benzyl)-6-(3′-methanesulfonyl-5′-trifluoromethyl-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,or a pharmaceutically acceptable salt of any of the foregoing.
 24. Thecompound of claim 21 wherein: n is 0; m is 1 or 2; R¹ is benzyloptionally substituted with one or more substituents independentlyselected from alkyl, halo or haloalkyl; R² is cyano; R³ istrifluoromethyl; each R⁵ is independently selected from the groupconsisting of alkyl, —R⁷—C(O)R¹¹, —R⁷—C(O)OR⁸ or —R⁷—C(O)N(R⁸)₂; R⁶ is adirect bond; each R⁷ is a direct bond; each R⁸ is independentlyhydrogen, alkyl, aryl or aralkyl; and R¹¹ is hydrogen, alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,pyrrolidinyl or piperidinyl.
 25. The compound of claim 24 selected fromthe group consisting of the following:6-(3′-Acetyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(4′-Acetyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-carboxylicacid amide;3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylicacid amide;3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-carboxylicacid dimethylamide;3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylicacid dimethylamide;1-(2,4-Difluoro-benzyl)-2-oxo-6-[3′-(pyrrolidine-1-carbonyl)-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-[4′-(piperidine-1-carbonyl)-biphenyl-3-yl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-carboxylicacid ethylamide;3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylicacid methylamide;3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylicacid phenylamide;3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-carboxylicacid benzylamide;{3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-yl}-aceticacid;{4′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-3-yl}-aceticacid;{3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-yl}-aceticacid;{4′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-yl}-aceticacid;{3-Chloro-3′-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-yl}-aceticacid methyl ester; and{3-Chloro-3′-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-biphenyl-4-yl}-aceticacid, or a pharmaceutically acceptable salt of any of the foregoing. 26.The compound of claim 21 wherein: n is 0; m is 0-2; R² is cyano; R³ istrifluoromethyl; each R⁵ is independently selected from the groupconsisting of halo, alkyl, alkenyl, haloalkyl or —R⁷—OR⁸; R⁶ is a directbond, a straight or branched alkenylene chain or a straight or branchedalkynylene chain; R⁷ is a direct bond; and R⁸ is hydrogen or alkyl. 27.The compound of claim 26 selected from the group consisting of thefollowing:6-(3′,5′-Bis-trifluoromethyl-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(3′,5′-Bis-trifluoromethyl-biphenyl-4-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(3′-Chloro-4′-ethoxy-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(3′,4′-dimethoxy-biphenyl-4-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(3′-Chloro-4′-ethoxy-biphenyl-4-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-(3-phenylethynyl-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-(4-phenylethynyl-phenyl)-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-2-oxo-6-[3-((E)-styryl)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;and1-(2,4-Difluoro-benzyl)-2-oxo-6-[4-((E)-styryl)-phenyl]-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile,or a pharmaceutically acceptable salt of any of the foregoing.
 28. Thecompound of claim 21 wherein: n is 0; m is 1 or 2; R² is cyano; R³ istrifluoromethyl; each R⁵ is independently selected from the groupconsisting of nitro, —R⁷—N(R⁸)₂, —R⁷—OR⁸ or —R⁷—N(R⁸)C(O)OR¹⁰; R⁶ is adirect bond; each R⁷ is a direct bond; each R⁸ is independently selectedfrom hydrogen or alkyl; and R¹⁰ is alkyl.
 29. The compound of claim 28selected from the group consisting of the following:6-(3′-Amino-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;1-(2,4-Difluoro-benzyl)-6-(4′-ethoxy-3′-nitro-biphenyl-3-yl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;6-(3′-Amino-4′-ethoxy-biphenyl-3-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile;and{3′-[5-Cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-4-ethoxy-biphenyl-3-yl}-carbamicacid tert-butyl ester, or a pharmaceutically acceptable salt of any ofthe foregoing.
 30. A method of reducing cholesterol levels in a subjectin need thereof, comprising administering an effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 31.A method of increasing cholesterol efflux from cells of a subject,comprising administering an effective amount of a compound of claim 1,or a pharmaceutically acceptable salt thereof.
 32. A method ofincreasing the expression of ATP-Binding Cassette (ABC1) in the cells ofa subject, comprising administering an effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 33. A method ofreducing cholesterol levels in a subject in need thereof, comprisingadministering an effective amount of a compound of claim
 1. 34. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of claim 1.